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| ID | Type | Description | Link |
|---|---|---|---|
| U01HL117659-01 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Heart, Lung, and Blood Institute (NHLBI) | NIH |
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The primary study hypothesis is that inhibition of factor Xa with rivaroxaban will reduce inflammation, coagulation and endothelial cell activation, and improve microvascular blood flow in patients with sickle cell disease (SCD) during the non-crisis, steady state. To test this hypothesis, this study will evaluate the effects of rivaroxaban on:
In a cross-over design, subjects will receive rivaroxaban 20 mg/day and placebo for 4 weeks each, separated by a 2-week washout phase.
The study will consist of a Screening Phase, two Treatment Phases, a Wash-Out Phase, and a Follow-up Phase. The Screening Phase will occur within 28 days of randomization and will include informed consent, a physical examination, and complete medical history to include determination of sickle cell genotype and current medications. Clinical laboratory tests to be performed include: a Complete Blood Count (CBC) with differential and reticulocyte count; Prothrombin time(PT) / activated partial thromboplastin time (aPTT); and serum chemistries (BUN, creatinine, total and direct bilirubin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, and LDH). A chest x-ray and MRI/MRA of the brain will also be done at Screening to rule out underlying disease.
If the patient is found through the screening process to be eligible, the 1st Treatment Phase begins. Baseline safety assessments and measurement of biomarkers are completed, then the subject is randomized to receive rivaroxaban or placebo. After 4 weeks of treatment, there is a 2-Week Wash-Out Phase. After the Wash-Out Phase, another set of baseline studies are performed and the 2nd Treatment Phase begins. For this Phase of the study, the subject "crosses over" to receive whatever treatment - rivaroxaban or placebo - that they did not receive in the 1st Treatment Phase. After taking the assigned study drug for 4 weeks, the 2nd Treatment Phase ends. The subject returns 2 weeks after the last dose of study treatment for the Follow-Up Phase, consisting of a single end-of-study visit during which safety assessments are repeated.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Rivaroxaban for 4 wks, Placebo for 4 wks | Other | Subject will receive rivaroxaban 20mg PO daily for 4 weeks and then matching placebo 1 PO daily for 4 weeks, with a 2-week wash out period in between the two treatment phases. Both of the two treatments will be in capsule form. |
|
| Placebo for 4 wks, rivaroxaban for 4 wks | Other | Subject will receive placebo 1 PO daily for 4 weeks, then rivaroxaban 20mg PO daily for 4 weeks, with a 2-week wash out period in between the two treatment phases. Both of the two treatments will be in capsule form. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| rivaroxaban | Drug | Subject will receive rivaroxaban 20mg PO daily for 4 weeks and then matching placebo 1 PO daily for 4 weeks, with a 2-week wash out period in between the two treatment phases. Both of the two treatments will be in capsule form OR Subject will receive placebo 1 PO daily for 4 weeks, then rivaroxaban 20mg PO daily for 4 weeks, with a 2-week wash out period in between the two treatment phases. Both of the two treatments will be in capsule form. |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline to 4 Weeks in Soluble Vascular Cell Adhesion Molecule-1 (VCAM-1) | Assay performed for soluble VCAM-1 using a commercially available enzyme-linked immunosorbent assay (ELISA). | Baseline, 4 weeks |
| Change From Baseline to 4 Weeks in Interleukin-6 (IL-6) | Assay performed for IL-6 using a commercially available enzyme-linked immunosorbent assay (ELISA). | Baseline, 4 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Change From Baseline to Week 4 in the Plasma Marker of Inflammation IL-2 | Interleukin-2 (IL-2) was measured using Luminex MAP technology at the UNC core facility | Baseline, 4 weeks |
| Change From Baseline to Week 4 in the Plasma Marker of Inflammation IL-8 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kenneth I Ataga, MBBS | University of North Carolina, Chapel Hill | Principal Investigator |
| Nigel Key, MD | University of North Carolina, Chapel Hill | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of North Carolina - Chapel Hill | Chapel Hill | North Carolina | 27599 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33660875 | Derived | Ataga KI, Elsherif L, Wichlan D, Wogu AF, Matsui N, Pawlinski R, Cai J, Key NS. A pilot study of the effect of rivaroxaban in sickle cell anemia. Transfusion. 2021 Jun;61(6):1694-1698. doi: 10.1111/trf.16343. Epub 2021 Mar 4. |
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15 subjects signed informed consent and were successfully screened. One subject withdrew during Baseline and prior to the first intervention and data from this individual are included in the baseline characteristics. One subject entered the second intervention period but was lost to follow up before receiving the intervention.
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| ID | Title | Description |
|---|---|---|
| FG000 | Rivaroxaban, Then Placebo | Participants first received Rivaroxaban 20 mg tablet once daily for 4 weeks. After a washout period of 2 weeks, they then received placebo (matching Rivaroxaban 20 mg tablet) once daily for 4 weeks. Rivaroxaban: 20 mg tablet by mouth daily for 4 weeks Placebo: Matching placebo tablet by mouth daily for 4 weeks |
| FG001 | Placebo, Then Rivaroxaban | Participants first received placebo (matching Rivaroxaban 20 mg tablet) once daily for 4 weeks. After a washout period of 2 weeks, they then received Rivaroxaban 20 mg tablet once daily for 4 weeks. Rivaroxaban: 20 mg tablet by mouth daily for 4 weeks Placebo: Matching placebo tablet by mouth daily for 4 weeks |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention |
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| Washout (2 Weeks) |
| |||||||||||||
| Second Intervention |
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All participants who had a screening visit
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| ID | Title | Description |
|---|---|---|
| BG000 | Study Participants | Participants who had a screening visit |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change From Baseline to 4 Weeks in Soluble Vascular Cell Adhesion Molecule-1 (VCAM-1) | Assay performed for soluble VCAM-1 using a commercially available enzyme-linked immunosorbent assay (ELISA). | Data reported only for those participants who completed both interventions. | Posted | Mean | 95% Confidence Interval | pg/mL | Baseline, 4 weeks |
|
Data collected from date of informed consent to end of study visit, approximately 3 months
The safety analysis population includes all participants exposed to any study intervention evaluated in this study.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Rivaroxaban | Participants who received Rivaroxaban 20 mg tablet in either the first or the second half of the study |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| painful crisis with bacteremia | Blood and lymphatic system disorders | Systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| pain crisis treated at home | Vascular disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Kenneth Ataga | University of Tennessee Center for the Heath Sciences | 901.448.3181 | kataga@uthsc.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Nov 20, 2015 | Mar 5, 2020 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D000755 | Anemia, Sickle Cell |
| D013927 | Thrombosis |
| ID | Term |
|---|---|
| D000745 | Anemia, Hemolytic, Congenital |
| D000743 | Anemia, Hemolytic |
| D000740 | Anemia |
| D006402 | Hematologic Diseases |
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| ID | Term |
|---|---|
| D000069552 | Rivaroxaban |
| ID | Term |
|---|---|
| D013876 | Thiophenes |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D009025 | Morpholines |
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|
| placebo | Drug | Subject will receive rivaroxaban 20mg PO daily for 4 weeks and then matching placebo 1 PO daily for 4 weeks, with a 2-week wash out period in between the two treatment phases. Both of the two treatments will be in capsule form OR Subject will receive placebo 1 PO daily for 4 weeks, then rivaroxaban 20mg PO daily for 4 weeks, with a 2-week wash out period in between the two treatment phases. Both of the two treatments will be in capsule form. |
|
Interleukin-8 (IL-8) was measured using Luminex MAP technology at the UNC core facility |
| Baseline, 4 weeks |
| Change From Baseline to Week 4 in Plasma Marker of Inflammation hsCRP | high sensitivity C-reactive protein (hsCRP) was measured using Luminex MAP technology at the UNC core facility. | Baseline, 4 weeks |
| Change From Baseline to Week 4 in Plasma Marker of Inflammation MPO | myeloperoxidase (MPO) was measured using Luminex MAP technology at the UNC core facility. | Baseline, 4 weeks |
| Change From Baseline to Week 4 in Plasma Marker of Inflammation TNF-a | tumor necrosis factor alpha (TNF-a) was measured using Luminex MAP technology at the UNC core facility. | Baseline, 4 weeks |
| Change From Baseline to Week 4 in Plasma Marker of Inflammation sPLA2 | secretory phospholipase A2 (sPLA2) was measured using Luminex MAP technology at the UNC core facility | Baseline, 4 weeks |
| Change From Baseline to Week 4 in Marker of Endothelial Cell (EC) Activation sICAM | levels of soluble intracellular adhesion molecule (sICAM) were measured using a commercially available ELISA | Baseline, 4 weeks |
| Change From Baseline to Week 4 in TH1 | Microvascular blood flow was measured using laser doppler velocimetry (LDV) assessments of post-occlusive reactive hyperemia (PORH). This was accomplished using the Perimed PF5001 Velocitometer (Stockholm, Sweden). Variable measured: time to half before hyperemia (TH1) | Baseline, 4 weeks |
| Change From Baseline to Week 4 in TM | Microvascular blood flow was measured using laser doppler velocimetry (LDV) assessments of post-occlusive reactive hyperemia (PORH). This was accomplished using the Perimed PF5001 Velocitometer (Stockholm, Sweden). Variable measured: time to max (TM) | Baseline, 4 weeks |
| Change From Baseline to Week 4 in AH | Microvascular blood flow was measured using laser doppler velocimetry (LDV) assessments of post-occlusive reactive hyperemia (PORH). This was accomplished using the Perimed PF5001 Velocitometer (Stockholm, Sweden). Variable measured: hyperemia area (AH) | Baseline, 4 weeks |
| Change in Ratio From Baseline to Week 4 in AH/AO | Microvascular blood flow was measured using laser doppler velocimetry (LDV) assessments of post-occlusive reactive hyperemia (PORH). This was accomplished using the Perimed PF5001 Velocitometer (Stockholm, Sweden). Variables measured: hyperemia area (AH) and occlusion area (AO) | Baseline, 4 weeks |
| Change From Baseline to Week 4 in PF | Microvascular blood flow was measured using laser doppler velocimetry (LDV) assessments of post-occlusive reactive hyperemia (PORH). This was accomplished using the Perimed PF5001 Velocitometer (Stockholm, Sweden). Variable measured: peak flow (PF) | Baseline, 4 weeks |
| Change From Baseline to Week 4 in RF | Microvascular blood flow was measured using laser doppler velocimetry (LDV) assessments of post-occlusive reactive hyperemia (PORH). This was accomplished using the Perimed PF5001 Velocitometer (Stockholm, Sweden). Variable measured: rest flow (RF) | Baseline, 4 weeks |
| Change From Baseline to Week 4 in TAT | Assay for thrombin antithrombin (TAT) complexes performed using commercially available enzyme-linked immunosorbent assay (ELISA). | Baseline, 4 weeks |
| Change From Baseline to Week 4 in D-Dimer | Assay for D--dimer is performed using commercially available enzyme-linked immunosorbent assay (ELISA). | Baseline, 4 weeks |
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| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Race (NIH/OMB) | Count of Participants | Participants |
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| Weight | Mean | Standard Deviation | kg |
|
| Height | Only measured on the participants who received study medication | Mean | Standard Deviation | cm |
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| White Blood Cell (WBC) count | Mean | Standard Deviation | 10^9 cells/L |
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| Genotype - Hemoglobin SS (HbSS) | Count of Participants | Participants |
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| Platelet count | Mean | Standard Deviation | 10^9 cells/L |
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| Serum Creatinine | Mean | Standard Deviation | mg/dL |
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| Prothrombin Time (PT) | A test that measures how quickly blood clots | Only measured on the participants who received study medication | Mean | Standard Deviation | sec |
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| International Normalized Ratio (INR) | The ratio of a patient's prothrombin time to a normal (control) sample | Only measured on the participants who received study medication | Mean | Standard Deviation | ratio |
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| Partial Thromboplastin Time (PTT) | Measures the time it takes for a blood clot to form | Only measured on the participants who received study medication | Mean | Standard Deviation | sec |
|
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| Primary | Change From Baseline to 4 Weeks in Interleukin-6 (IL-6) | Assay performed for IL-6 using a commercially available enzyme-linked immunosorbent assay (ELISA). | Data reported only for those participants who completed both interventions. | Posted | Mean | 95% Confidence Interval | pg/mL | Baseline, 4 weeks |
|
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|
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| Secondary | Change From Baseline to Week 4 in the Plasma Marker of Inflammation IL-2 | Interleukin-2 (IL-2) was measured using Luminex MAP technology at the UNC core facility | Data analyzed for the 13 participants completing both interventions but results for 6 participants in each group fell outside the standard curve and could not be extrapolated. | Posted | Mean | 95% Confidence Interval | pg/mL | Baseline, 4 weeks |
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| Secondary | Change From Baseline to Week 4 in the Plasma Marker of Inflammation IL-8 | Interleukin-8 (IL-8) was measured using Luminex MAP technology at the UNC core facility | Data analyzed for the 13 participants completing both interventions but results for 4 participants in the rivaroxaban group and 5 participants in the placebo group fell outside the standard curve and could not be extrapolated. | Posted | Mean | 95% Confidence Interval | pg/mL | Baseline, 4 weeks |
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| Secondary | Change From Baseline to Week 4 in Plasma Marker of Inflammation hsCRP | high sensitivity C-reactive protein (hsCRP) was measured using Luminex MAP technology at the UNC core facility. | Biomarker evaluations were limited to IL-2 and IL-8 as those were thought more likely to reflect inflammation activation based on experience in recent studies. | Posted | Baseline, 4 weeks |
|
|
| Secondary | Change From Baseline to Week 4 in Plasma Marker of Inflammation MPO | myeloperoxidase (MPO) was measured using Luminex MAP technology at the UNC core facility. | Biomarker evaluations were limited to IL-2 and IL-8 as those were thought more likely to reflect inflammation activation based on experience in recent studies. | Posted | Baseline, 4 weeks |
|
|
| Secondary | Change From Baseline to Week 4 in Plasma Marker of Inflammation TNF-a | tumor necrosis factor alpha (TNF-a) was measured using Luminex MAP technology at the UNC core facility. | Biomarker evaluations were limited to IL-2 and IL-8 as those were thought more likely to reflect inflammation activation based on experience in recent studies. | Posted | Baseline, 4 weeks |
|
|
| Secondary | Change From Baseline to Week 4 in Plasma Marker of Inflammation sPLA2 | secretory phospholipase A2 (sPLA2) was measured using Luminex MAP technology at the UNC core facility | Biomarker evaluations were limited to IL-2 and IL-8 as those were thought more likely to reflect inflammation activation based on experience in recent studies. | Posted | Baseline, 4 weeks |
|
|
| Secondary | Change From Baseline to Week 4 in Marker of Endothelial Cell (EC) Activation sICAM | levels of soluble intracellular adhesion molecule (sICAM) were measured using a commercially available ELISA | Biomarker evaluations were limited to VCAM-1 and IL-6 as those were thought more likely to reflect endothelial cell activation based on experience in recent studies. | Posted | Baseline, 4 weeks |
|
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| Secondary | Change From Baseline to Week 4 in TH1 | Microvascular blood flow was measured using laser doppler velocimetry (LDV) assessments of post-occlusive reactive hyperemia (PORH). This was accomplished using the Perimed PF5001 Velocitometer (Stockholm, Sweden). Variable measured: time to half before hyperemia (TH1) | All participants randomized to each treatment were analyzed. | Posted | Mean | 95% Confidence Interval | seconds | Baseline, 4 weeks |
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| Secondary | Change From Baseline to Week 4 in TM | Microvascular blood flow was measured using laser doppler velocimetry (LDV) assessments of post-occlusive reactive hyperemia (PORH). This was accomplished using the Perimed PF5001 Velocitometer (Stockholm, Sweden). Variable measured: time to max (TM) | All participants randomized to each treatment were analyzed. | Posted | Mean | 95% Confidence Interval | seconds | Baseline, 4 weeks |
|
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|
|
| Secondary | Change From Baseline to Week 4 in AH | Microvascular blood flow was measured using laser doppler velocimetry (LDV) assessments of post-occlusive reactive hyperemia (PORH). This was accomplished using the Perimed PF5001 Velocitometer (Stockholm, Sweden). Variable measured: hyperemia area (AH) | All participants randomized to each treatment were analyzed. | Posted | Mean | 95% Confidence Interval | perfusion units*seconds | Baseline, 4 weeks |
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|
|
| Secondary | Change in Ratio From Baseline to Week 4 in AH/AO | Microvascular blood flow was measured using laser doppler velocimetry (LDV) assessments of post-occlusive reactive hyperemia (PORH). This was accomplished using the Perimed PF5001 Velocitometer (Stockholm, Sweden). Variables measured: hyperemia area (AH) and occlusion area (AO) | All participants randomized to each treatment were analyzed. | Posted | Mean | 95% Confidence Interval | ratio of AH to AO | Baseline, 4 weeks |
|
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|
| Secondary | Change From Baseline to Week 4 in PF | Microvascular blood flow was measured using laser doppler velocimetry (LDV) assessments of post-occlusive reactive hyperemia (PORH). This was accomplished using the Perimed PF5001 Velocitometer (Stockholm, Sweden). Variable measured: peak flow (PF) | All participants randomized to each treatment were analyzed. | Posted | Mean | 95% Confidence Interval | perfusion units | Baseline, 4 weeks |
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| Secondary | Change From Baseline to Week 4 in RF | Microvascular blood flow was measured using laser doppler velocimetry (LDV) assessments of post-occlusive reactive hyperemia (PORH). This was accomplished using the Perimed PF5001 Velocitometer (Stockholm, Sweden). Variable measured: rest flow (RF) | All participants randomized to each treatment were analyzed. | Posted | Mean | 95% Confidence Interval | perfusion units | Baseline, 4 weeks |
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| Secondary | Change From Baseline to Week 4 in TAT | Assay for thrombin antithrombin (TAT) complexes performed using commercially available enzyme-linked immunosorbent assay (ELISA). | Data reported only for those participants who completed both interventions. | Posted | Mean | 95% Confidence Interval | ug/mL | Baseline, 4 weeks |
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| Secondary | Change From Baseline to Week 4 in D-Dimer | Assay for D--dimer is performed using commercially available enzyme-linked immunosorbent assay (ELISA). | Data reported only for those participants who completed both interventions. | Posted | Mean | 95% Confidence Interval | ng/mL | Baseline, 4 weeks |
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| 0 |
| 14 |
| 1 |
| 14 |
| 8 |
| 14 |
| EG001 | Placebo | Participants who received placebo tablet (matching Rivaroxaban 20 mg) in either the first or the second half of the study | 0 | 13 | 1 | 13 | 7 | 13 |
| pneumonia | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
|
| headache | General disorders | Systematic Assessment |
|
| chest pain | General disorders | Systematic Assessment |
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| back pain | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| neutropenia | Blood and lymphatic system disorders | Systematic Assessment |
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| ankle laceration | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| tick bite | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| diarrhea, nausea and vomiting | Gastrointestinal disorders | Systematic Assessment |
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| insomnia | General disorders | Systematic Assessment |
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| tinea versicolor | Skin and subcutaneous tissue disorders | Systematic Assessment |
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| elevate liver enzymes | Gastrointestinal disorders | Systematic Assessment |
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| cough, fever, body aches, congestion | Respiratory, thoracic and mediastinal disorders | Systematic Assessment |
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| pain in lower extremities | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| dyspnea | General disorders | Systematic Assessment |
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| pelvic pressure with urination | Renal and urinary disorders | Systematic Assessment |
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| right flank pain | General disorders | Systematic Assessment |
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| D006425 |
| Hemic and Lymphatic Diseases |
| D006453 | Hemoglobinopathies |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D016769 | Embolism and Thrombosis |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D010078 |
| Oxazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |