The Effect of Rivaroxaban in Sickle Cell Disease

• 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: University of North Carolina, Chapel Hill
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI)
• Information provided by (Responsible Party): University of North Carolina, Chapel Hill

Tracking Information

• First Submitted Date: February 24, 2014
• First Posted Date: February 26, 2014
• Results First Submitted Date: March 18, 2020
• Results First Posted Date: April 13, 2020
• Last Update Posted Date: April 13, 2020
• Study Start Date: February 2014
• Actual Primary Completion Date: October 4, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 9, 2020)

• 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).
• 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).

Original Primary Outcome Measures (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).

Current Secondary Outcome Measures (submitted: April 9, 2020)

• 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
• 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
• 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.
• 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.
• 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.
• 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
• 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
• 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)
• 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)
• 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)
• 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)
• 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)
• 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)
• 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).
• 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).

Original Secondary Outcome Measures (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: The Effect of Rivaroxaban in Sickle Cell Disease
• Official Title: 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: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment

Condition

• Sickle Cell Anemia
• Sickle Cell-Beta0-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.
  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

• 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 *: Ataga KI, Elsherif L, Wichlan D, Wogu AF, Matsui N, Pawlinski R, Cai J, Key NS. A pilot study of the effect of rivaroxaban in sickle cell anemia. Transfusion. 2021 Jun;61(6):1694-1698. doi: 10.1111/trf.16343. Epub 2021 Mar 4.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 8, 2019): 14
• Original Estimated Enrollment (submitted: February 25, 2014): 34
• Actual Study Completion Date: October 4, 2018
• Actual Primary Completion Date: October 4, 2018 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02072668
• Other Study ID Numbers: 12-2607; U01HL117659-01 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: University of North Carolina, Chapel Hill
• Original Responsible Party: Kenneth Ataga, MD, University of North Carolina, Chapel Hill, Associate Professor of Medicine, Director, UNC Comprehensive Sickle Cell Program
• Current Study Sponsor: University of North Carolina, Chapel Hill
• Original Study Sponsor: Same as current
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• 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: March 2020