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The Effect of Rivaroxaban in Sickle Cell Disease

This study is enrolling participants by invitation only.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02072668
First Posted: February 26, 2014
Last Update Posted: October 31, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill
  Purpose

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 Intervention Phase
Sickle Cell Anemia Sickle Cell-Beta0-Thalassemia Drug: rivaroxaban Drug: placebo Phase 2

Study Type: Interventional
Study Design: 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

Resource links provided by NLM:


Further study details as provided by University of North Carolina, Chapel Hill:

Primary Outcome Measures:
  • Change from baseline to 4 weeks in soluble vascular cell adhesion molecule-1 (VCAM-1) and interleukin-6 (IL-6) [ Time Frame: Screening, Baseline, 2 weeks, 4 weeks ]
    Assays for soluble VCAM-1 and IL-6 are performed using a commercially available enzyme-linked immunosorbent assay (ELISA).


Secondary Outcome Measures:
  • Change from Baseline to Week 4 in other plasma markers of inflammation. [ Time Frame: Screening, Baseline, 2 weeks and 4 weeks ]
    The following inflammatory markers will be measured: high sensitivity C-reactive protein (hsCRP), myeloperoxidase (MPO), interleukin-2 (IL-2), interleukin-8 (IL-8), tumor necrosis factor-alpha (TNFα), and secretory phospholipase A2 (sPLA2) using Luminex MAP technology at the UNC core facility.

  • Change from baseline to Week 4 in other markers of endothelial cell (EC) activation. [ Time Frame: Screening, Baseline, 2 weeks, 4 weeks ]
    To assess EC activation, levels of soluble intracellular adhesion molecule (sICAM) are measured using a commercially available ELISA.

  • Change from baseline to Week 4 in microvascular blood flow [ Time Frame: Baseline and 4 weeks ]
    Microvascular blood flow is measured using laser doppler velocimetry (LDV) assessments of post-occlusive reactive hyperemia (PORH). This is accomplished using the Perimed PF5001 Velocitometer (Stockholm, Sweden).

  • Change from baseline to Week 4 in markers of coagulation activation. [ Time Frame: Screening, Baseline, 2 weeks, 4 weeks ]
    Assays for thrombin antithrombin complexes and D--dimer are performed using commercially available enzyme-linked immunosorbent assays (ELISA).


Estimated Enrollment: 34
Study Start Date: February 2014
Estimated Study Completion Date: May 2018
Estimated Primary Completion Date: May 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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.
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 Name: 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.

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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02072668


Locations
United States, North Carolina
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
  More Information

Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT02072668     History of Changes
Other Study ID Numbers: 12-2607
U01HL117659-01 ( U.S. NIH Grant/Contract )
First Submitted: February 24, 2014
First Posted: February 26, 2014
Last Update Posted: October 31, 2017
Last Verified: October 2017

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
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Rivaroxaban
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants