- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02072668
The Effect of Rivaroxaban in Sickle Cell Disease
The Effect of Factor Xa Inhibition, With Rivaroxaban, on the Pathology of Sickle Cell Disease
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.
Study Overview
Status
Conditions
Intervention / Treatment
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
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
North Carolina
-
Chapel Hill, North Carolina, United States, 27599
- University of North Carolina - Chapel Hill
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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.
Study Plan
How is the study designed?
Design Details
- Primary Purpose: TREATMENT
- Allocation: RANDOMIZED
- Interventional Model: CROSSOVER
- Masking: QUADRUPLE
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
OTHER: 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.
|
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 Names:
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: 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.
|
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 Names:
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.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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).
|
Baseline, 4 weeks
|
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).
|
Baseline, 4 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
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
|
Baseline, 4 weeks
|
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
|
Baseline, 4 weeks
|
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.
|
Baseline, 4 weeks
|
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.
|
Baseline, 4 weeks
|
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.
|
Baseline, 4 weeks
|
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
|
Baseline, 4 weeks
|
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
|
Baseline, 4 weeks
|
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)
|
Baseline, 4 weeks
|
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)
|
Baseline, 4 weeks
|
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)
|
Baseline, 4 weeks
|
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)
|
Baseline, 4 weeks
|
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)
|
Baseline, 4 weeks
|
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)
|
Baseline, 4 weeks
|
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).
|
Baseline, 4 weeks
|
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).
|
Baseline, 4 weeks
|
Collaborators and Investigators
Collaborators
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (ACTUAL)
Study Completion (ACTUAL)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (ESTIMATE)
Study Record Updates
Last Update Posted (ACTUAL)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Hematologic Diseases
- Genetic Diseases, Inborn
- Anemia
- Anemia, Hemolytic, Congenital
- Anemia, Hemolytic
- Hemoglobinopathies
- Anemia, Sickle Cell
- Thalassemia
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Protease Inhibitors
- Factor Xa Inhibitors
- Antithrombins
- Serine Proteinase Inhibitors
- Anticoagulants
- Rivaroxaban
Other Study ID Numbers
- 12-2607
- U01HL117659-01 (NIH)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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