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The Effect of Rivaroxaban in Sickle Cell Disease

Primary Purpose

Sickle Cell Anemia, Sickle Cell-Beta0-Thalassemia

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
rivaroxaban
placebo
Sponsored by
University of North Carolina, Chapel Hill
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sickle Cell Anemia focused on measuring sickle cell anemia, sickle cell disease, rivaroxaban, direct Xa inhibition, coagulation, anticoagulation

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of North Carolina - Chapel Hill

Arms of the Study

Arm 1

Arm 2

Arm Type

Other

Other

Arm Label

Rivaroxaban for 4 wks, Placebo for 4 wks

Placebo for 4 wks, rivaroxaban for 4 wks

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

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).
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).

Secondary Outcome Measures

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
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
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.
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.
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.
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
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
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)
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)
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)
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)
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)
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)
Change From Baseline to Week 4 in TAT
Assay for thrombin antithrombin (TAT) complexes performed using commercially available enzyme-linked immunosorbent assay (ELISA).
Change From Baseline to Week 4 in D-Dimer
Assay for D--dimer is performed using commercially available enzyme-linked immunosorbent assay (ELISA).

Full Information

First Posted
February 24, 2014
Last Updated
April 9, 2020
Sponsor
University of North Carolina, Chapel Hill
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT02072668
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
Study Type
Interventional

2. Study Status

Record Verification Date
March 2020
Overall Recruitment Status
Completed
Study Start Date
February 2014 (undefined)
Primary Completion Date
October 4, 2018 (Actual)
Study Completion Date
October 4, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of North Carolina, Chapel Hill
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sickle Cell Anemia, Sickle Cell-Beta0-Thalassemia
Keywords
sickle cell anemia, sickle cell disease, rivaroxaban, direct Xa inhibition, coagulation, anticoagulation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
14 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Rivaroxaban for 4 wks, Placebo for 4 wks
Arm Type
Other
Arm Description
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.
Arm Title
Placebo for 4 wks, rivaroxaban for 4 wks
Arm Type
Other
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
rivaroxaban
Other Intervention Name(s)
Xarelto
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
placebo
Intervention Description
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 Measure Information:
Title
Change From Baseline to 4 Weeks in Soluble Vascular Cell Adhesion Molecule-1 (VCAM-1)
Description
Assay performed for soluble VCAM-1 using a commercially available enzyme-linked immunosorbent assay (ELISA).
Time Frame
Baseline, 4 weeks
Title
Change From Baseline to 4 Weeks in Interleukin-6 (IL-6)
Description
Assay performed for IL-6 using a commercially available enzyme-linked immunosorbent assay (ELISA).
Time Frame
Baseline, 4 weeks
Secondary Outcome Measure Information:
Title
Change From Baseline to Week 4 in the Plasma Marker of Inflammation IL-2
Description
Interleukin-2 (IL-2) was measured using Luminex MAP technology at the UNC core facility
Time Frame
Baseline, 4 weeks
Title
Change From Baseline to Week 4 in the Plasma Marker of Inflammation IL-8
Description
Interleukin-8 (IL-8) was measured using Luminex MAP technology at the UNC core facility
Time Frame
Baseline, 4 weeks
Title
Change From Baseline to Week 4 in Plasma Marker of Inflammation hsCRP
Description
high sensitivity C-reactive protein (hsCRP) was measured using Luminex MAP technology at the UNC core facility.
Time Frame
Baseline, 4 weeks
Title
Change From Baseline to Week 4 in Plasma Marker of Inflammation MPO
Description
myeloperoxidase (MPO) was measured using Luminex MAP technology at the UNC core facility.
Time Frame
Baseline, 4 weeks
Title
Change From Baseline to Week 4 in Plasma Marker of Inflammation TNF-a
Description
tumor necrosis factor alpha (TNF-a) was measured using Luminex MAP technology at the UNC core facility.
Time Frame
Baseline, 4 weeks
Title
Change From Baseline to Week 4 in Plasma Marker of Inflammation sPLA2
Description
secretory phospholipase A2 (sPLA2) was measured using Luminex MAP technology at the UNC core facility
Time Frame
Baseline, 4 weeks
Title
Change From Baseline to Week 4 in Marker of Endothelial Cell (EC) Activation sICAM
Description
levels of soluble intracellular adhesion molecule (sICAM) were measured using a commercially available ELISA
Time Frame
Baseline, 4 weeks
Title
Change From Baseline to Week 4 in TH1
Description
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)
Time Frame
Baseline, 4 weeks
Title
Change From Baseline to Week 4 in TM
Description
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)
Time Frame
Baseline, 4 weeks
Title
Change From Baseline to Week 4 in AH
Description
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)
Time Frame
Baseline, 4 weeks
Title
Change in Ratio From Baseline to Week 4 in AH/AO
Description
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)
Time Frame
Baseline, 4 weeks
Title
Change From Baseline to Week 4 in PF
Description
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)
Time Frame
Baseline, 4 weeks
Title
Change From Baseline to Week 4 in RF
Description
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)
Time Frame
Baseline, 4 weeks
Title
Change From Baseline to Week 4 in TAT
Description
Assay for thrombin antithrombin (TAT) complexes performed using commercially available enzyme-linked immunosorbent assay (ELISA).
Time Frame
Baseline, 4 weeks
Title
Change From Baseline to Week 4 in D-Dimer
Description
Assay for D--dimer is performed using commercially available enzyme-linked immunosorbent assay (ELISA).
Time Frame
Baseline, 4 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Kenneth I Ataga, MBBS
Organizational Affiliation
University of North Carolina, Chapel Hill
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Nigel Key, MD
Organizational Affiliation
University of North Carolina, Chapel Hill
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of North Carolina - Chapel Hill
City
Chapel Hill
State/Province
North Carolina
ZIP/Postal Code
27599
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
33660875
Citation
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.
Results Reference
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The Effect of Rivaroxaban in Sickle Cell Disease

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