Sickle Cell Disease
Conditions
Keywords
Venous thrombosis, Protein disulfide isomerase, Thrombo-inflammation, HbS polymerization, P-selectin
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.
Interventions
DRUGIsoquercetin
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.
DRUGPlacebo
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.
Sponsors
Quercis Pharma AG
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in the Plasma Soluble P-selectin Level | Baseline and Day 28 | Mean change in plasma soluble P-selectin level comparing the baseline versus IQ or placebo. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change in Vascular Cell Adhesion Molecule | Baseline and Day 28 | Mean Change in Vascular Cell Adhesion Molecule (inflammation marker) comparing baseline to Day 28 |
| Mean Change in Plasma Protein Disulfide Isomerase Activity | Baseline and 28 days | Mean Change in Plasma Protein Disulfide Isomerase Activity comparing baseline and end of study |
| Median Change of Tissue Factor Vesicle Number | Baseline and Day 28 | Median change of Tissue Factor Vesicle Number comparing baseline and end of study |
| Mean Change in Tissue Factor Vesicle Procoagulant Activity | Baseline and Day 28 | Mean change in tissue factor vesicle procoagulant activity comparing baseline and end of study |
| Mean Change in D-Dimer | Baseline and Day 28 | Mean Change in D-Dimer comparing baseline and end of study |
| Mean Percent Adherence to Study Drug | Baseline and Day 28 | 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. |
| Number of Adverse Events Grade 2 and Above | Up to Day 56 | Number of adverse events Grade 2 and above using Common Terminology Criteria for Adverse Events (CTCAE) 5.0 |
| Number of Participants That Tolerated Study Drug | Up to day 28 | Number of participants that tolerated study drug for full duration of study |
| Median Relative Blood Flow Index (rBFI) Determined by Near-infrared Spectroscopy (NIRS) | Day 28 | 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)\]. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Participants With Sickle Cell Disease Receiving Isoquercetin Isoquercetin given 1000 mg, once daily by mouth for 28 days in participants with Sickle Cell Disease. | 23 |
| Participants With Sickle Cell Disease Receiving Placebo Placebo given once daily, by mouth for 28 days in participants with Sickle Cell Disease. | 23 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Randomized but did not receive Isoquercetin | 1 | 0 |
Baseline characteristics
| Characteristic | Participants With Sickle Cell Disease Receiving Isoquercetin | Participants With Sickle Cell Disease Receiving Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants | 22 Participants | 45 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 20 Participants | 42 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 21 Participants | 22 Participants | 43 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 23 participants | 23 participants | 46 participants |
| Sex: Female, Male Female | 12 Participants | 14 Participants | 26 Participants |
| Sex: Female, Male Male | 11 Participants | 9 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 23 |
| other Total, other adverse events | 9 / 23 | 11 / 23 |
| serious Total, serious adverse events | 6 / 23 | 4 / 23 |
Outcome results
Primary
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
Population: One patient in the isoquercetin arm was randomized but withdrawn from the study before any treatment and did not provide baseline soluble P-selectin measurement nor contribute to this analysis. One patient in the placebo arm provided baseline soluble P-selectin and their change in P-selectin was obtained via a multiple imputation procedure. 45 participants (22 isoquercetin and 23 placebo) contributed to the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Sickle Cell Disease Receiving Isoquercetin | Mean Change in the Plasma Soluble P-selectin Level | 0.74 ng/ml | Standard Deviation 6.53 |
| Participants With Sickle Cell Disease Receiving Placebo | Mean Change in the Plasma Soluble P-selectin Level | 0.10 ng/ml | Standard Deviation 4.54 |
p-value: 0.64ANCOVA with Multiple Imputation
Secondary
Mean Change in D-Dimer
Mean Change in D-Dimer comparing baseline and end of study
Time frame: Baseline and Day 28
Population: Analysis includes only participants that completed study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Sickle Cell Disease Receiving Isoquercetin | Mean Change in D-Dimer | 0.15 mcg/mL | Standard Deviation 0.92 |
| Participants With Sickle Cell Disease Receiving Placebo | Mean Change in D-Dimer | 0.28 mcg/mL | Standard Deviation 1.18 |
Secondary
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
Population: Analysis includes only participants that completed study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Sickle Cell Disease Receiving Isoquercetin | Mean Change in Plasma Protein Disulfide Isomerase Activity | -3.13 pMoles/min/µL | Standard Deviation 10.91 |
| Participants With Sickle Cell Disease Receiving Placebo | Mean Change in Plasma Protein Disulfide Isomerase Activity | 1.95 pMoles/min/µL | Standard Deviation 9.34 |
Secondary
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
Population: Analysis includes only participants that completed study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Sickle Cell Disease Receiving Isoquercetin | Mean Change in Tissue Factor Vesicle Procoagulant Activity | -427 Picomoles | Standard Deviation 1868 |
| Participants With Sickle Cell Disease Receiving Placebo | Mean Change in Tissue Factor Vesicle Procoagulant Activity | -43 Picomoles | Standard Deviation 1404 |
Secondary
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
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Sickle Cell Disease Receiving Isoquercetin | Mean Change in Vascular Cell Adhesion Molecule | -22.43 ng/mL | Standard Deviation 291.42 |
| Participants With Sickle Cell Disease Receiving Placebo | Mean Change in Vascular Cell Adhesion Molecule | -38.15 ng/mL | Standard Deviation 180.24 |
Secondary
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
Population: Analysis includes only participants that completed study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants With Sickle Cell Disease Receiving Isoquercetin | Mean Percent Adherence to Study Drug | 96.2 percentage of adherence | Standard Deviation 13.9 |
| Participants With Sickle Cell Disease Receiving Placebo | Mean Percent Adherence to Study Drug | 97.2 percentage of adherence | Standard Deviation 4.7 |
Secondary
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
Population: Analysis includes only participants that completed study
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Participants With Sickle Cell Disease Receiving Isoquercetin | Median Change of Tissue Factor Vesicle Number | 39 microvesicles/mL |
| Participants With Sickle Cell Disease Receiving Placebo | Median Change of Tissue Factor Vesicle Number | -382 microvesicles/mL |
Secondary
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
Population: Analysis includes those participants that completed the end of study Near-infrared spectroscopy (NIRS) procedure.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Participants With Sickle Cell Disease Receiving Isoquercetin | Median Relative Blood Flow Index (rBFI) Determined by Near-infrared Spectroscopy (NIRS) | 0.00000000082 (cm2/s)/s |
| Participants With Sickle Cell Disease Receiving Placebo | Median Relative Blood Flow Index (rBFI) Determined by Near-infrared Spectroscopy (NIRS) | 0.00000000037 (cm2/s)/s |
p-value: 0.149Wilcoxon (Mann-Whitney)
Secondary
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Participants With Sickle Cell Disease Receiving Isoquercetin | Number of Adverse Events Grade 2 and Above | Grade 2 | 8 Adverse Events |
| Participants With Sickle Cell Disease Receiving Isoquercetin | Number of Adverse Events Grade 2 and Above | Grade 3 and 4 | 1 Adverse Events |
| Participants With Sickle Cell Disease Receiving Isoquercetin | Number of Adverse Events Grade 2 and Above | Serious Adverse Events | 8 Adverse Events |
| Participants With Sickle Cell Disease Receiving Placebo | Number of Adverse Events Grade 2 and Above | Grade 2 | 9 Adverse Events |
| Participants With Sickle Cell Disease Receiving Placebo | Number of Adverse Events Grade 2 and Above | Grade 3 and 4 | 2 Adverse Events |
| Participants With Sickle Cell Disease Receiving Placebo | Number of Adverse Events Grade 2 and Above | Serious Adverse Events | 6 Adverse Events |
Secondary
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
Population: Analysis includes only participants that completed study
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Participants With Sickle Cell Disease Receiving Isoquercetin | Number of Participants That Tolerated Study Drug | 22 Participants |
| Participants With Sickle Cell Disease Receiving Placebo | Number of Participants That Tolerated Study Drug | 22 Participants |