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The Effect of Rivaroxaban in Sickle Cell Disease

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ClinicalTrials.gov Identifier: NCT02072668
Recruitment Status : Completed
First Posted : February 26, 2014
Last Update Posted : February 11, 2019
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

Tracking Information
First Submitted Date  ICMJE February 24, 2014
First Posted Date  ICMJE February 26, 2014
Last Update Posted Date February 11, 2019
Study Start Date  ICMJE February 2014
Actual Primary Completion Date December 31, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 27, 2014)
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).
Original Primary Outcome Measures  ICMJE
 (submitted: February 25, 2014)
Change from baseline to 4 weeks in markers of coagulation. [ Time Frame: Screening, Baseline, 2 weeks, 4 weeks ]
To measure activation of coagulation, assays for thrombin-antithrombin complex (TAT) and D-dimer are performed using a commercially available enzyme-linked immunosorbent assay (ELISA).
Change History Complete list of historical versions of study NCT02072668 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 27, 2014)
  • 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).
Original Secondary Outcome Measures  ICMJE
 (submitted: February 25, 2014)
  • Change from Baseline to Week 4 in markers of inflammation. [ Time Frame: Screening, Baseline, 2 weeks and 4 weeks ]
    The following inflammatory markers will be measured: interleukin-6 (IL-6), using a commercially available ELISA; and 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 markers of endothelial cell (EC) activation. [ Time Frame: Screening, Baseline, 2 weeks, 4 weeks ]
    To assess EC activation, levels of soluble vascular cell adhesion molecule (sVCAM) and 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).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Effect of Rivaroxaban in Sickle Cell Disease
Official Title  ICMJE The Effect of Factor Xa Inhibition, With Rivaroxaban, on the Pathology of Sickle Cell Disease
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Sickle Cell Anemia
  • Sickle Cell-Beta0-Thalassemia
Intervention  ICMJE
  • 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.
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: rivaroxaban
    • Drug: placebo
  • 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.
    Interventions:
    • Drug: rivaroxaban
    • Drug: placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 8, 2019)
14
Original Estimated Enrollment  ICMJE
 (submitted: February 25, 2014)
34
Actual Study Completion Date  ICMJE December 31, 2018
Actual Primary Completion Date December 31, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02072668
Other Study ID Numbers  ICMJE 12-2607
U01HL117659-01 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University of North Carolina, Chapel Hill
Study Sponsor  ICMJE University of North Carolina, Chapel Hill
Collaborators  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Investigators  ICMJE
Principal Investigator: Kenneth I Ataga, MBBS University of North Carolina, Chapel Hill
Principal Investigator: Nigel Key, MD University of North Carolina, Chapel Hill
PRS Account University of North Carolina, Chapel Hill
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP