The Effect of Rivaroxaban in Sickle Cell Disease

• Sponsor: University of North Carolina, Chapel Hill (Other)
• Overall Status: Completed
• CT.gov ID: NCT02072668
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 14
• Location: 1
• Arms: 2
• Duration (Months): 56
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

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:

• plasma markers of inflammation;

• plasma markers of endothelial activation;

• plasma markers of thrombin generation; and

• microvascular blood flow assessed using laser Doppler velocimetry (LDV) of post-occlusive reactive hyperemia (PORH).

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.

Condition or Disease	Intervention/Treatment	Phase
Sickle Cell Anemia; Sickle Cell-Beta0-Thalassemia	Drug: rivaroxaban; Drug: placebo	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 14 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Effect of Factor Xa Inhibition, With Rivaroxaban, on the Pathology of Sickle Cell Disease
• Study Start Date: Feb 1, 2014
• Actual Primary Completion Date: Oct 4, 2018
• Actual Study Completion Date: Oct 4, 2018

Arms and Interventions

Arm	Intervention/Treatment
Other: Rivaroxaban for 4 wks, Placebo for 4 wks 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.	Drug: rivaroxaban; 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.; Other Names: Xarelto ; Drug: placebo; 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.
Other: Placebo for 4 wks, rivaroxaban for 4 wks 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.	Drug: rivaroxaban; 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.; Other Names: Xarelto ; Drug: placebo; 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.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to 4 Weeks in Soluble Vascular Cell Adhesion Molecule-1 (VCAM-1) [Baseline, 4 weeks]

   Assay performed for soluble VCAM-1 using a commercially available enzyme-linked immunosorbent assay (ELISA).

2. Change From Baseline to 4 Weeks in Interleukin-6 (IL-6) [Baseline, 4 weeks]

   Assay performed for IL-6 using a commercially available enzyme-linked immunosorbent assay (ELISA).

Secondary Outcome Measures

1. Change From Baseline to Week 4 in the Plasma Marker of Inflammation IL-2 [Baseline, 4 weeks]

   Interleukin-2 (IL-2) was measured using Luminex MAP technology at the UNC core facility

2. Change From Baseline to Week 4 in the Plasma Marker of Inflammation IL-8 [Baseline, 4 weeks]

   Interleukin-8 (IL-8) was measured using Luminex MAP technology at the UNC core facility

3. Change From Baseline to Week 4 in Plasma Marker of Inflammation hsCRP [Baseline, 4 weeks]

   high sensitivity C-reactive protein (hsCRP) was measured using Luminex MAP technology at the UNC core facility.

4. Change From Baseline to Week 4 in Plasma Marker of Inflammation MPO [Baseline, 4 weeks]

   myeloperoxidase (MPO) was measured using Luminex MAP technology at the UNC core facility.

5. Change From Baseline to Week 4 in Plasma Marker of Inflammation TNF-a [Baseline, 4 weeks]

   tumor necrosis factor alpha (TNF-a) was measured using Luminex MAP technology at the UNC core facility.

6. Change From Baseline to Week 4 in Plasma Marker of Inflammation sPLA2 [Baseline, 4 weeks]

   secretory phospholipase A2 (sPLA2) was measured using Luminex MAP technology at the UNC core facility

7. Change From Baseline to Week 4 in Marker of Endothelial Cell (EC) Activation sICAM [Baseline, 4 weeks]

   levels of soluble intracellular adhesion molecule (sICAM) were measured using a commercially available ELISA

8. Change From Baseline to Week 4 in TH1 [Baseline, 4 weeks]

   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)

9. Change From Baseline to Week 4 in TM [Baseline, 4 weeks]

   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)

10. Change From Baseline to Week 4 in AH [Baseline, 4 weeks]

    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)

11. Change in Ratio From Baseline to Week 4 in AH/AO [Baseline, 4 weeks]

    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)

12. Change From Baseline to Week 4 in PF [Baseline, 4 weeks]

    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)

13. Change From Baseline to Week 4 in RF [Baseline, 4 weeks]

    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)

14. Change From Baseline to Week 4 in TAT [Baseline, 4 weeks]

    Assay for thrombin antithrombin (TAT) complexes performed using commercially available enzyme-linked immunosorbent assay (ELISA).

15. Change From Baseline to Week 4 in D-Dimer [Baseline, 4 weeks]

    Assay for D--dimer is performed using commercially available enzyme-linked immunosorbent assay (ELISA).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 18 to 65 years of age; sickle cell anemia (HbSS) or sickle-beta0 (HbSβ0) thalassemia;

• serum creatinine ≤ 1.0 mg/dL men) or 1.2 mg/dL (women);

• ALT </= 2 times upper limits of normal;

• platelet count ≥ 50,000 cu/mm;

• normal baseline PT/international normalized ratio (INR) and aPTT;

• be in the non-crisis, "steady state" with no severe pain episodes during the preceding 4 weeks;

• ability to understand the requirements of the study and be willing to give informed consent;

• women of childbearing age must be practicing an adequate method of contraception;

• and if on hydroxyurea, be on a stable dose for at least 3 months prior to enrollment.

Exclusion Criteria:

• hypersensitivity to any component of rivaroxaban;

• history of major GI bleeding or bleeding diathesis;

• baseline Hb < 5.5 gm/dL;

• history of clinically overt stroke;

• brain magnetic resonance imaging with angiography (MRI/MRA) scan with evidence of Moya Moya;

• pregnant or breastfeeding;

• active liver disease or ALT > 3 times upper limit of normal;

• on chronic anticoagulant, non-steroidal anti-inflammatory (NSAID) or statin therapy;

• history of metastatic cancer;

• current alcohol abuse;

• on a chronic transfusion program or any blood transfusion in the 3 months prior to enrollment;

• ingested any investigational drugs within the past 4 weeks;

• use of CYP3A4/P-glycoprotein inducers such as carbamazepine, phenytoin, rifampin, and St John's wort;

• use of CYP3A4/P- glycoprotein inhibitors such as ketoconazole, indinavir/ritonavir, itraconazole, lopinavir/ritonavir, ritonavir, and conivaptan.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of North Carolina - Chapel Hill	Chapel Hill	North Carolina	United States	27599

Sponsors and Collaborators

• University of North Carolina, Chapel Hill
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: Kenneth I Ataga, MBBS, University of North Carolina, Chapel Hill
• Principal Investigator: Nigel Key, MD, University of North Carolina, Chapel Hill

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Nov 20, 2015

More Information

Publications

None provided.

• Responsible Party: University of North Carolina, Chapel Hill
• ClinicalTrials.gov Identifier: NCT02072668
• Other Study ID Numbers: 12-2607; U01HL117659-01
• First Posted: Feb 26, 2014
• Last Update Posted: Apr 13, 2020
• Last Verified: Mar 1, 2020

• Keywords provided by University of North Carolina, Chapel Hill: sickle cell anemia; sickle cell disease; rivaroxaban; direct Xa inhibition; coagulation; anticoagulation
• Additional relevant MeSH terms: Anemia, Sickle Cell; Thalassemia; Rivaroxaban

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	Rivaroxaban, Then Placebo	Placebo, Then Rivaroxaban
Arm/Group Description	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	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
Period Title: First Intervention
STARTED	7	7
COMPLETED	7	7
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	7	7
COMPLETED	7	7
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	7	7
COMPLETED	6	7
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Study Participants
Arm/Group Description	Participants who had a screening visit
Overall Participants	15
Age, Customized (years) [Mean (Standard Deviation) ]
Age	39.00 (10.95)
Sex: Female, Male (Count of Participants)
Female	9 60%
Male	6 40%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	15 100%
White	0 0%
More than one race	0 0%
Unknown or Not Reported	0 0%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	68.22 (11.69)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	169.40 (10.56)
White Blood Cell (WBC) count (10^9 cells/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [10^9 cells/L]	8.49 (2.03)
Genotype - Hemoglobin SS (HbSS) (Count of Participants)
Count of Participants [Participants]	15 100%
Platelet count (10^9 cells/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [10^9 cells/L]	370.07 (169.13)
Serum Creatinine (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	0.7 (0.22)
Prothrombin Time (PT) (sec) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [sec]	12.54 (0.99)
International Normalized Ratio (INR) (ratio) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ratio]	1.13 (0.09)
Partial Thromboplastin Time (PTT) (sec) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [sec]	27.16 (2.48)

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to 4 Weeks in Soluble Vascular Cell Adhesion Molecule-1 (VCAM-1)
Description	Assay performed for soluble VCAM-1 using a commercially available enzyme-linked immunosorbent assay (ELISA).
Time Frame	Baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

Data reported only for those participants who completed both interventions.

Arm/Group Title	Rivaroxaban	Placebo
Arm/Group Description	Participants who received Rivaroxaban 20 mg tablet in either the first or the second half of the study	Participants who received placebo tablet (matching Rivaroxaban 20 mg) in either the first or the second half of the study
Measure Participants	13	13
Mean (95% Confidence Interval) [pg/mL]	40.9	10.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6281
	Comments
	Method	Student t-test followed by ANOVA
	Comments	Student t-test subsequently followed by crossover ANOVA model testing carry-over effect and treatment effect

2. Primary Outcome

Title	Change From Baseline to 4 Weeks in Interleukin-6 (IL-6)
Description	Assay performed for IL-6 using a commercially available enzyme-linked immunosorbent assay (ELISA).
Time Frame	Baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

Data reported only for those participants who completed both interventions.

Arm/Group Title	Rivaroxaban	Placebo
Arm/Group Description	Participants who received Rivaroxaban 20 mg tablet in either the first or the second half of the study	Participants who received placebo tablet (matching Rivaroxaban 20 mg) in either the first or the second half of the study
Measure Participants	13	13
Mean (95% Confidence Interval) [pg/mL]	-1.1	-0.54

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7973
	Comments
	Method	Student t-test followed by ANOVA
	Comments	Student t-test subsequently followed by crossover ANOVA model testing carry-over effect and treatment effect

3. Secondary Outcome

Title	Change From Baseline to Week 4 in the Plasma Marker of Inflammation IL-2
Description	Interleukin-2 (IL-2) was measured using Luminex MAP technology at the UNC core facility
Time Frame	Baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Rivaroxaban	Placebo
Arm/Group Description	Participants who received Rivaroxaban 20 mg tablet in either the first or the second half of the study	Participants who received placebo tablet (matching Rivaroxaban 20 mg) in either the first or the second half of the study
Measure Participants	7	7
Mean (95% Confidence Interval) [pg/mL]	-1.14	0.36

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4442
	Comments
	Method	Student t-test followed by ANOVA
	Comments	Student t-test subsequently followed by crossover ANOVA model testing carry-over effect and treatment effect

4. Secondary Outcome

Title	Change From Baseline to Week 4 in the Plasma Marker of Inflammation IL-8
Description	Interleukin-8 (IL-8) was measured using Luminex MAP technology at the UNC core facility
Time Frame	Baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Rivaroxaban	Placebo
Arm/Group Description	Participants who received Rivaroxaban 20 mg tablet in either the first or the second half of the study	Participants who received placebo tablet (matching Rivaroxaban 20 mg) in either the first or the second half of the study
Measure Participants	9	8
Mean (95% Confidence Interval) [pg/mL]	0.95	-4.08

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2545
	Comments
	Method	Student t-test followed by ANOVA
	Comments	Student t-test subsequently followed by crossover ANOVA model testing carry-over effect and treatment effect

5. Secondary Outcome

Title	Change From Baseline to Week 4 in Plasma Marker of Inflammation hsCRP
Description	high sensitivity C-reactive protein (hsCRP) was measured using Luminex MAP technology at the UNC core facility.
Time Frame	Baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Rivaroxaban	Placebo
Arm/Group Description	Participants who received Rivaroxaban 20 mg tablet in either the first or the second half of the study	Participants who received placebo tablet (matching Rivaroxaban 20 mg) in either the first or the second half of the study
Measure Participants	0	0

6. Secondary Outcome

Title	Change From Baseline to Week 4 in Plasma Marker of Inflammation MPO
Description	myeloperoxidase (MPO) was measured using Luminex MAP technology at the UNC core facility.
Time Frame	Baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Rivaroxaban	Placebo
Arm/Group Description	Participants who received Rivaroxaban 20 mg tablet in either the first or the second half of the study	Participants who received placebo tablet (matching Rivaroxaban 20 mg) in either the first or the second half of the study
Measure Participants	0	0

7. Secondary Outcome

Title	Change From Baseline to Week 4 in Plasma Marker of Inflammation TNF-a
Description	tumor necrosis factor alpha (TNF-a) was measured using Luminex MAP technology at the UNC core facility.
Time Frame	Baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Rivaroxaban	Placebo
Arm/Group Description	Participants who received Rivaroxaban 20 mg tablet in either the first or the second half of the study	Participants who received placebo tablet (matching Rivaroxaban 20 mg) in either the first or the second half of the study
Measure Participants	0	0

8. Secondary Outcome

Title	Change From Baseline to Week 4 in Plasma Marker of Inflammation sPLA2
Description	secretory phospholipase A2 (sPLA2) was measured using Luminex MAP technology at the UNC core facility
Time Frame	Baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Rivaroxaban	Placebo
Arm/Group Description	Participants who received Rivaroxaban 20 mg tablet in either the first or the second half of the study	Participants who received placebo tablet (matching Rivaroxaban 20 mg) in either the first or the second half of the study
Measure Participants	0	0

9. Secondary Outcome

Title	Change From Baseline to Week 4 in Marker of Endothelial Cell (EC) Activation sICAM
Description	levels of soluble intracellular adhesion molecule (sICAM) were measured using a commercially available ELISA
Time Frame	Baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Rivaroxaban, Then Placebo	Placebo, Then Rivaroxaban
Arm/Group Description	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	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
Measure Participants	0	0

10. Secondary Outcome

Title	Change From Baseline to Week 4 in TH1
Description	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)
Time Frame	Baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

All participants randomized to each treatment were analyzed.

Arm/Group Title	Rivaroxaban	Placebo
Arm/Group Description	Participants who received Rivaroxaban 20 mg tablet in either the first or the second half of the study	Participants who received placebo tablet (matching Rivaroxaban 20 mg) in either the first or the second half of the study
Measure Participants	14	13
Mean (95% Confidence Interval) [seconds]	0.84	-0.51

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4374
	Comments
	Method	Student t-test followed by ANOVA
	Comments	Student t-test subsequently followed by crossover ANOVA model testing carry-over effect and treatment effect

11. Secondary Outcome

Title	Change From Baseline to Week 4 in TM
Description	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)
Time Frame	Baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

All participants randomized to each treatment were analyzed.

Arm/Group Title	Rivaroxaban	Placebo
Arm/Group Description	Participants who received Rivaroxaban 20 mg tablet in either the first or the second half of the study	Participants who received placebo tablet (matching Rivaroxaban 20 mg) in either the first or the second half of the study
Measure Participants	14	13
Mean (95% Confidence Interval) [seconds]	-0.97	-2.01

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3470
	Comments
	Method	Student t-test followed by ANOVA
	Comments	Student t-test subsequently followed by crossover ANOVA model testing carry-over effect and treatment effect

12. Secondary Outcome

Title	Change From Baseline to Week 4 in AH
Description	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)
Time Frame	Baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

All participants randomized to each treatment were analyzed.

Arm/Group Title	Rivaroxaban	Placebo
Arm/Group Description	Participants who received Rivaroxaban 20 mg tablet in either the first or the second half of the study	Participants who received placebo tablet (matching Rivaroxaban 20 mg) in either the first or the second half of the study
Measure Participants	14	13
Mean (95% Confidence Interval) [perfusion units*seconds]	128	-1189

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0755
	Comments
	Method	Student t-test followed by ANOVA
	Comments	Student t-test subsequently followed by crossover ANOVA model testing carry-over effect and treatment effect

13. Secondary Outcome

Title	Change in Ratio From Baseline to Week 4 in AH/AO
Description	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)
Time Frame	Baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

All participants randomized to each treatment were analyzed.

Arm/Group Title	Rivaroxaban	Placebo
Arm/Group Description	Participants who received Rivaroxaban 20 mg tablet in either the first or the second half of the study	Participants who received placebo tablet (matching Rivaroxaban 20 mg) in either the first or the second half of the study
Measure Participants	14	13
Mean (95% Confidence Interval) [ratio of AH to AO]	0.05	-0.81

14. Secondary Outcome

Title	Change From Baseline to Week 4 in PF
Description	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)
Time Frame	Baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

All participants randomized to each treatment were analyzed.

Arm/Group Title	Rivaroxaban	Placebo
Arm/Group Description	Participants who received Rivaroxaban 20 mg tablet in either the first or the second half of the study	Participants who received placebo tablet (matching Rivaroxaban 20 mg) in either the first or the second half of the study
Measure Participants	14	13
Mean (95% Confidence Interval) [perfusion units]	3.14	-12.62

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0708
	Comments
	Method	Student t-test followed by ANOVA
	Comments	Student t-test subsequently followed by crossover ANOVA model testing carry-over effect and treatment effect

15. Secondary Outcome

Title	Change From Baseline to Week 4 in RF
Description	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)
Time Frame	Baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

All participants randomized to each treatment were analyzed.

Arm/Group Title	Rivaroxaban	Placebo
Arm/Group Description	Participants who received Rivaroxaban 20 mg tablet in either the first or the second half of the study	Participants who received placebo tablet (matching Rivaroxaban 20 mg) in either the first or the second half of the study
Measure Participants	14	13
Mean (95% Confidence Interval) [perfusion units]	0.29	-0.62

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4501
	Comments
	Method	Student t-test followed by ANOVA
	Comments	Student t-test subsequently followed by crossover ANOVA model testing carry-over effect and treatment effect

16. Secondary Outcome

Title	Change From Baseline to Week 4 in TAT
Description	Assay for thrombin antithrombin (TAT) complexes performed using commercially available enzyme-linked immunosorbent assay (ELISA).
Time Frame	Baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

Data reported only for those participants who completed both interventions.

Arm/Group Title	Rivaroxaban	Placebo
Arm/Group Description	Participants who received Rivaroxaban 20 mg tablet in either the first or the second half of the study	Participants who received placebo tablet (matching Rivaroxaban 20 mg) in either the first or the second half of the study
Measure Participants	13	13
Mean (95% Confidence Interval) [ug/mL]	-34.44	0.35

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0767
	Comments
	Method	Student t-test followed by ANOVA
	Comments	Student t-test subsequently followed by crossover ANOVA model testing carry-over effect and treatment effect

17. Secondary Outcome

Title	Change From Baseline to Week 4 in D-Dimer
Description	Assay for D--dimer is performed using commercially available enzyme-linked immunosorbent assay (ELISA).
Time Frame	Baseline, 4 weeks

Outcome Measure Data

Analysis Population Description

Data reported only for those participants who completed both interventions.

Arm/Group Title	Rivaroxaban	Placebo
Arm/Group Description	Participants who received Rivaroxaban 20 mg tablet in either the first or the second half of the study	Participants who received placebo tablet (matching Rivaroxaban 20 mg) in either the first or the second half of the study
Measure Participants	13	13
Mean (95% Confidence Interval) [ng/mL]	-471	-1035

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rivaroxaban, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7250
	Comments
	Method	Student t-test followed by ANOVA
	Comments	Student t-test subsequently followed by crossover ANOVA model testing carry-over effect and treatment effect

Adverse Events

Time Frame	Data collected from date of informed consent to end of study visit, approximately 3 months
Adverse Event Reporting Description	The safety analysis population includes all participants exposed to any study intervention evaluated in this study.
Arm/Group Title	Rivaroxaban		Placebo
Arm/Group Description	Participants who received Rivaroxaban 20 mg tablet in either the first or the second half of the study		Participants who received placebo tablet (matching Rivaroxaban 20 mg) in either the first or the second half of the study
All Cause Mortality
	Rivaroxaban		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/14 (0%)		0/13 (0%)
Serious Adverse Events
	Rivaroxaban		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/14 (7.1%)		1/13 (7.7%)
Blood and lymphatic system disorders
painful crisis with bacteremia	0/14 (0%)	0	1/13 (7.7%)	1
Respiratory, thoracic and mediastinal disorders
pneumonia	1/14 (7.1%)	1	0/13 (0%)	0
Other (Not Including Serious) Adverse Events
	Rivaroxaban		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/14 (57.1%)		7/13 (53.8%)
Blood and lymphatic system disorders
neutropenia	1/14 (7.1%)	1	2/13 (15.4%)	3
Gastrointestinal disorders
diarrhea, nausea and vomiting	2/14 (14.3%)	3	0/13 (0%)	0
elevate liver enzymes	0/14 (0%)	0	1/13 (7.7%)	1
General disorders
headache	2/14 (14.3%)	2	1/13 (7.7%)	1
chest pain	3/14 (21.4%)	3	0/13 (0%)	0
insomnia	1/14 (7.1%)	1	0/13 (0%)	0
dyspnea	1/14 (7.1%)	1	0/13 (0%)	0
right flank pain	1/14 (7.1%)	1	0/13 (0%)	0
Musculoskeletal and connective tissue disorders
back pain	1/14 (7.1%)	1	1/13 (7.7%)	1
pain in lower extremities	1/14 (7.1%)	1	1/13 (7.7%)	1
Renal and urinary disorders
pelvic pressure with urination	1/14 (7.1%)	1	0/13 (0%)	0
Respiratory, thoracic and mediastinal disorders
cough, fever, body aches, congestion	1/14 (7.1%)	1	2/13 (15.4%)	2
Skin and subcutaneous tissue disorders
ankle laceration	0/14 (0%)	0	1/13 (7.7%)	1
tick bite	1/14 (7.1%)	1	0/13 (0%)	0
tinea versicolor	1/14 (7.1%)	1	0/13 (0%)	0
Vascular disorders
pain crisis treated at home	4/14 (28.6%)	6	2/13 (15.4%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.