The Effect of Rivaroxaban in Sickle Cell Disease

Phase 2

Completed

Conditions: Sickle Cell Anemia
Sickle Cell-Beta0-Thalassemia

Interventions: Drug: rivaroxaban
Drug: placebo

Registration Number: NCT02072668

Lead Sponsor: University of North Carolina, Chapel Hill

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 14

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Rivaroxaban for 4 wks, Placebo for 4 wks	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.
Rivaroxaban for 4 wks, Placebo for 4 wks	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.
Placebo for 4 wks, rivaroxaban for 4 wks	placebo	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.
Placebo for 4 wks, rivaroxaban for 4 wks	rivaroxaban	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.

Primary Outcome Measures

Name	Time	Method
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).
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

Name	Time	Method
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
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
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)
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)
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.
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.
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.
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
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
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)
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)
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)
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)
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).
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).