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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
Results First Posted : April 13, 2020
Last Update Posted : April 13, 2020
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
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.


Condition or disease Intervention/treatment Phase
Sickle Cell Anemia Sickle Cell-Beta0-Thalassemia Drug: rivaroxaban Drug: placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
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
Study Start Date : February 2014
Actual Primary Completion Date : October 4, 2018
Actual Study Completion Date : October 4, 2018

Resource links provided by the National Library of Medicine

Drug Information available for: Rivaroxaban

Arm Intervention/treatment
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.




Primary Outcome Measures :
  1. Change From Baseline to 4 Weeks in Soluble Vascular Cell Adhesion Molecule-1 (VCAM-1) [ Time Frame: Baseline, 4 weeks ]
    Assay performed for soluble VCAM-1 using a commercially available enzyme-linked immunosorbent assay (ELISA).

  2. Change From Baseline to 4 Weeks in Interleukin-6 (IL-6) [ Time Frame: Baseline, 4 weeks ]
    Assay performed for IL-6 using a commercially available enzyme-linked immunosorbent assay (ELISA).


Secondary Outcome Measures :
  1. Change From Baseline to Week 4 in the Plasma Marker of Inflammation IL-2 [ Time Frame: Baseline, 4 weeks ]
    Interleukin-2 (IL-2) was measured using Luminex MAP technology at the UNC core facility

  2. Change From Baseline to Week 4 in the Plasma Marker of Inflammation IL-8 [ Time Frame: Baseline, 4 weeks ]
    Interleukin-8 (IL-8) was measured using Luminex MAP technology at the UNC core facility

  3. Change From Baseline to Week 4 in Plasma Marker of Inflammation hsCRP [ Time Frame: Baseline, 4 weeks ]
    high sensitivity C-reactive protein (hsCRP) was measured using Luminex MAP technology at the UNC core facility.

  4. Change From Baseline to Week 4 in Plasma Marker of Inflammation MPO [ Time Frame: Baseline, 4 weeks ]
    myeloperoxidase (MPO) was measured using Luminex MAP technology at the UNC core facility.

  5. Change From Baseline to Week 4 in Plasma Marker of Inflammation TNF-a [ Time Frame: Baseline, 4 weeks ]
    tumor necrosis factor alpha (TNF-a) was measured using Luminex MAP technology at the UNC core facility.

  6. Change From Baseline to Week 4 in Plasma Marker of Inflammation sPLA2 [ Time Frame: Baseline, 4 weeks ]
    secretory phospholipase A2 (sPLA2) was measured using Luminex MAP technology at the UNC core facility

  7. Change From Baseline to Week 4 in Marker of Endothelial Cell (EC) Activation sICAM [ Time Frame: Baseline, 4 weeks ]
    levels of soluble intracellular adhesion molecule (sICAM) were measured using a commercially available ELISA

  8. Change From Baseline to Week 4 in TH1 [ Time Frame: 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)

  9. Change From Baseline to Week 4 in TM [ Time Frame: 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)

  10. Change From Baseline to Week 4 in AH [ Time Frame: 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)

  11. Change in Ratio From Baseline to Week 4 in AH/AO [ Time Frame: 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)

  12. Change From Baseline to Week 4 in PF [ Time Frame: 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)

  13. Change From Baseline to Week 4 in RF [ Time Frame: 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)

  14. Change From Baseline to Week 4 in TAT [ Time Frame: Baseline, 4 weeks ]
    Assay for thrombin antithrombin (TAT) complexes performed using commercially available enzyme-linked immunosorbent assay (ELISA).

  15. Change From Baseline to Week 4 in D-Dimer [ Time Frame: Baseline, 4 weeks ]
    Assay for D--dimer is performed using commercially available enzyme-linked immunosorbent assay (ELISA).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older 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.

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
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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
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Principal Investigator: Kenneth I Ataga, MBBS University of North Carolina, Chapel Hill
Principal Investigator: Nigel Key, MD University of North Carolina, Chapel Hill
  Study Documents (Full-Text)

Documents provided by University of North Carolina, Chapel Hill:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT02072668    
Other Study ID Numbers: 12-2607
U01HL117659-01 ( U.S. NIH Grant/Contract )
First Posted: February 26, 2014    Key Record Dates
Results First Posted: April 13, 2020
Last Update Posted: April 13, 2020
Last Verified: March 2020
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:
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Anemia, Sickle Cell
Thalassemia
Anemia
Hematologic Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Hemoglobinopathies
Genetic Diseases, Inborn
Rivaroxaban
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants