Clinical trial NCT04514510: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Sickle Cell Disease
Keywords: Venous thrombosis
Protein disulfide isomerase
Thrombo-inflammation
HbS polymerization
P-selectin
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
Collaborators: name: Quercis Pharma AG
First posted: 2020-08-17
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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 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.

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, 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.

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.

Primary outcomes:
measure: Mean Change in the Plasma Soluble P-selectin Level
timeFrame: Baseline and Day 28
Secondary outcomes:
measure: Mean Change in Plasma Protein Disulfide Isomerase Activity
timeFrame: Baseline and 28 days
measure: Median Change of Tissue Factor Vesicle Number
timeFrame: Baseline and Day 28
measure: Mean Change in Tissue Factor Vesicle Procoagulant Activity
timeFrame: Baseline and Day 28
measure: Mean Change in D-Dimer
timeFrame: Baseline and Day 28
measure: Mean Change in Vascular Cell Adhesion Molecule
timeFrame: Baseline and Day 28
measure: Median Relative Blood Flow Index (rBFI) Determined by Near-infrared Spectroscopy (NIRS)
timeFrame: Day 28
measure: Mean Percent Adherence to Study Drug
timeFrame: Baseline and Day 28
measure: Number of Adverse Events Grade 2 and Above
timeFrame: Up to Day 56
measure: Number of Participants That Tolerated Study Drug
timeFrame: Up to day 28
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
name: Arun S Shet, M.D.
role: PRINCIPAL_INVESTIGATOR
References: