The Effect of Rivaroxaban in Sickle Cell Disease

Sickle Cell Anemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02072668
• Other study ID #: 12-2607
• Secondary ID: U01HL117659-01
• Status: Completed
• Phase: Phase 2
• Start date: February 2014
• Est. completion date: October 4, 2018

Study information

• Verified date: March 2020
• Source: University of North Carolina, Chapel Hill
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 14
• Est. completion date: October 4, 2018
• Est. primary completion date: October 4, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• 18 to 65 years of age; sickle cell anemia (HbSS) or sickle-beta0 (HbSß0) 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.

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Anemia
• Sickle Cell-Beta0-Thalassemia
• Thalassemia

Intervention

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.
• 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.

Locations

Country	Name	City	State
United States	University of North Carolina - Chapel Hill	Chapel Hill	North Carolina

Sponsors (2)

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

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
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).	Baseline, 4 weeks
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).	Baseline, 4 weeks
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	Baseline, 4 weeks
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	Baseline, 4 weeks
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.	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.	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.	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	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	Baseline, 4 weeks
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)	Baseline, 4 weeks
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)	Baseline, 4 weeks
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)	Baseline, 4 weeks
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)	Baseline, 4 weeks
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)	Baseline, 4 weeks
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)	Baseline, 4 weeks
Secondary	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
Secondary	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