Fixed Dose Flavonoid Isoquercetin on Thrombo-Inflammatory Biomarkers in Subjects With Stable Sickle Cell Disease

• ClinicalTrials.gov Identifier: NCT04514510
• Recruitment Status: Recruiting
• First Posted: August 17, 2020
• Last Update Posted: May 20, 2022
• Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Tracking Information

• First Submitted Date: August 14, 2020
• First Posted Date: August 17, 2020
• Last Update Posted Date: May 20, 2022
• Actual Study Start Date: November 2, 2020
• Estimated Primary Completion Date: September 30, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 20, 2021)

The primary outcome will be the change in the plasma soluble P-selectin level comparing the baseline to IQ response [ Time Frame: 28 days ]

The primary outcome will be the change in plasma soluble P-selectin level comparing the baseline versus IQ or placebo.

Original Primary Outcome Measures (submitted: August 14, 2020)

The primary outcome will be the change in the plasma soluble P-selectin level comparing the baseline to IQ response [ Time Frame: 28 days ]

The primary outcome will be the change in the plasma soluble P-selectin level comparing the baseline versus IQ or placebo.

Current Secondary Outcome Measures (submitted: August 15, 2020)

• plasma protein disulfide isomerase activity [ Time Frame: 28 days ]
  Compare baseline and end of study plasma protein disulfide isomerase activity
• tissue factor positive extracellular vesicle number [ Time Frame: 28 days ]
  Compare baseline and end of study plasma tissue factor positive extracellular vesicle number
• procoagulant activity [ Time Frame: 28 days ]
  Compare baseline and end of study plasma tissue factor procoagulant activity
• inflammation and coagulation parameters [ Time Frame: 28 days ]
  Compare baseline and end of study inflammation and coagulation parameters
• biomarkers of vascular function and atherothrombosis [ Time Frame: 28 days ]
  Compare baseline and end of study contemporary biomarkers of vascular function and atherothrombosis
• safety/tolerability and adherence to oral IQ [ Time Frame: 28 days ]
  Assess safety/tolerability and adherence to oral IQ

Original Secondary Outcome Measures (submitted: August 14, 2020)

• plasma protein disulfide isomerase activity [ Time Frame: 28 days ]
  Compare baseline and end of study plasma protein disulfide isomerase activity
• tissue factor positive extracellular vesicle number [ Time Frame: 28 days ]
  Compare baseline and end of study plasma tissue factor positive extracellular vesicle number
• procoagulant activity [ Time Frame: 28 days ]
  Compare baseline and end of study plasma tissue factor procoagulant activity
• inflammation and coagulation parameters [ Time Frame: 8 days ]
  Compare baseline and end of study inflammation and coagulation parameters
• biomarkers of vascular function and atherothrombosis [ Time Frame: 28 days ]
  Compare baseline and end of study contemporary biomarkers of vascular function and atherothrombosis
• safety/tolerability and adherence to oral IQ [ Time Frame: 28 days ]
  Assess safety/tolerability and adherence to oral IQ

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Fixed Dose Flavonoid Isoquercetin on Thrombo-Inflammatory Biomarkers in Subjects With Stable Sickle Cell Disease
• Official Title: A Study to Evaluate the Effects of Fixed Dose Flavonoid Isoquercetin on Thrombo-Inflammatory Biomarkers in Subjects With Stable Sickle Cell Disease

Brief Summary

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.

Detailed Description

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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Basic Science
• Condition: VTE

Intervention

• Drug: Isoquercetin
  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.
• Drug: Placebo
  Silicified microcrystalline cellulose NF, Ascorbic acid, Nicotinic acid, Mg stearate, Silica and Colloidal Anhydrous Ph. Eur./Colloidal Silicon dioxide USP/NF

Study Arms

• Experimental: ISO
  Subjects with sickle cell disease; Isoquercetin 1000mg once daily 28 days.
  Intervention: Drug: Isoquercetin
• Placebo Comparator: Placebo
  Subjects with sickle cell disease; placebo once daily for 28 days.
  Intervention: Drug: Placebo

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: August 14, 2020): 60
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 28, 2022
• Estimated Primary Completion Date: September 30, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

• 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 an optimized dose for at least 30 days. For those newly initiated on HU therapy, the dose should be unchanged for at least 90 days.
• 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:

• 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 46 Years (Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Mai Hill, R.N.; (301) 402-2105; mai.hill@nih.gov

Contact: Arun S Shet, M.D.; (301) 827-6808; arun.shet@nih.gov

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT04514510
• Other Study ID Numbers: 200137; 20-H-0137
• Has Data Monitoring Committee: Not Provided

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
• Study Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Collaborators: Not Provided

Investigators

• Principal Investigator: Arun S Shet, M.D.; National Heart, Lung, and Blood Institute (NHLBI)

• PRS Account: National Institutes of Health Clinical Center (CC)
• Verification Date: February 23, 2022