The Effect of Rivaroxaban in Sickle Cell Disease

Study Overview
=================
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.

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.

Official Title
-----------------
The Effect of Factor Xa Inhibition, With Rivaroxaban, on the Pathology of Sickle Cell Disease

Conditions
-----------------
Sickle Cell Anemia, Sickle Cell-Beta0-Thalassemia

Intervention / Treatment
-----------------
* Drug: rivaroxaban
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Rivaroxaban for 4 wks, Placebo for 4 wks<br>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<br>* 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.<br>* Other names: Xarelto;Drug: placebo<br>* 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.<br>|
| Other: Placebo for 4 wks, rivaroxaban for 4 wks<br>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<br>* 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.<br>* Other names: Xarelto;Drug: placebo<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | 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 | 

Secondary Outcome Measures

| Outcome Measure | 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 | 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
sickle cell anemia, sickle cell disease, rivaroxaban, direct Xa inhibition, coagulation, anticoagulation