Sickle Cell Anemia, Sickle Cell-Beta0-Thalassemia
Conditions
Keywords
sickle cell anemia, sickle cell disease, rivaroxaban, direct Xa inhibition, coagulation, anticoagulation
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.
Interventions
DRUGrivaroxaban
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.
DRUGplacebo
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.
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 4 Weeks in Soluble Vascular Cell Adhesion Molecule-1 (VCAM-1) | 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) | Baseline, 4 weeks | Assay performed for IL-6 using a commercially available enzyme-linked immunosorbent assay (ELISA). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 4 in Plasma Marker of Inflammation hsCRP | 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 | 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 | 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 | 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 | 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 | 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 the Plasma Marker of Inflammation IL-2 | 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 AH | 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 | 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 | 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 | 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 | 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 | Baseline, 4 weeks | Assay for D--dimer is performed using commercially available enzyme-linked immunosorbent assay (ELISA). |
| Change From Baseline to Week 4 in TM | 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 the Plasma Marker of Inflammation IL-8 | Baseline, 4 weeks | Interleukin-8 (IL-8) was measured using Luminex MAP technology at the UNC core facility |
Countries
United States
Participant flow
Pre-assignment details
15 subjects signed informed consent and were successfully screened. One subject withdrew during Baseline and prior to the first intervention and data from this individual are included in the baseline characteristics. One subject entered the second intervention period but was lost to follow up before receiving the intervention.
Participants by arm
| Arm | Count |
|---|---|
| Study Participants Participants who had a screening visit | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Second Intervention | Lost to Follow-up | 1 | 0 |
Baseline characteristics
| Characteristic | Study Participants |
|---|---|
| Age, Customized Age | 39.00 years STANDARD_DEVIATION 10.95 |
| Genotype - Hemoglobin SS (HbSS) | 15 Participants |
| Height | 169.40 cm STANDARD_DEVIATION 10.56 |
| International Normalized Ratio (INR) | 1.13 ratio STANDARD_DEVIATION 0.09 |
| Partial Thromboplastin Time (PTT) | 27.16 sec STANDARD_DEVIATION 2.48 |
| Platelet count | 370.07 10^9 cells/L STANDARD_DEVIATION 169.13 |
| Prothrombin Time (PT) | 12.54 sec STANDARD_DEVIATION 0.99 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Serum Creatinine | 0.7 mg/dL STANDARD_DEVIATION 0.22 |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 6 Participants |
| Weight | 68.22 kg STANDARD_DEVIATION 11.69 |
| White Blood Cell (WBC) count | 8.49 10^9 cells/L STANDARD_DEVIATION 2.03 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 13 |
| other Total, other adverse events | 8 / 14 | 7 / 13 |
| serious Total, serious adverse events | 1 / 14 | 1 / 13 |
Outcome results
Primary
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).
Time frame: Baseline, 4 weeks
Population: Data reported only for those participants who completed both interventions.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Rivaroxaban | Change From Baseline to 4 Weeks in Interleukin-6 (IL-6) | -1.1 pg/mL |
| Placebo | Change From Baseline to 4 Weeks in Interleukin-6 (IL-6) | -0.54 pg/mL |
p-value: 0.7973Student t-test followed by ANOVA
Primary
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).
Time frame: Baseline, 4 weeks
Population: Data reported only for those participants who completed both interventions.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Rivaroxaban | Change From Baseline to 4 Weeks in Soluble Vascular Cell Adhesion Molecule-1 (VCAM-1) | 40.9 pg/mL |
| Placebo | Change From Baseline to 4 Weeks in Soluble Vascular Cell Adhesion Molecule-1 (VCAM-1) | 10.7 pg/mL |
p-value: 0.6281Student t-test followed by ANOVA
Secondary
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)
Time frame: Baseline, 4 weeks
Population: All participants randomized to each treatment were analyzed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Rivaroxaban | Change From Baseline to Week 4 in AH | 128 perfusion units*seconds |
| Placebo | Change From Baseline to Week 4 in AH | -1189 perfusion units*seconds |
p-value: 0.0755Student t-test followed by ANOVA
Secondary
Change From Baseline to Week 4 in D-Dimer
Assay for D--dimer is performed using commercially available enzyme-linked immunosorbent assay (ELISA).
Time frame: Baseline, 4 weeks
Population: Data reported only for those participants who completed both interventions.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Rivaroxaban | Change From Baseline to Week 4 in D-Dimer | -471 ng/mL |
| Placebo | Change From Baseline to Week 4 in D-Dimer | -1035 ng/mL |
p-value: 0.725Student t-test followed by ANOVA
Secondary
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
Time frame: Baseline, 4 weeks
Population: Biomarker evaluations were limited to VCAM-1 and IL-6 as those were thought more likely to reflect endothelial cell activation based on experience in recent studies.
Secondary
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)
Time frame: Baseline, 4 weeks
Population: All participants randomized to each treatment were analyzed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Rivaroxaban | Change From Baseline to Week 4 in PF | 3.14 perfusion units |
| Placebo | Change From Baseline to Week 4 in PF | -12.62 perfusion units |
p-value: 0.0708Student t-test followed by ANOVA
Secondary
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.
Time frame: Baseline, 4 weeks
Population: Biomarker evaluations were limited to IL-2 and IL-8 as those were thought more likely to reflect inflammation activation based on experience in recent studies.
Secondary
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.
Time frame: Baseline, 4 weeks
Population: Biomarker evaluations were limited to IL-2 and IL-8 as those were thought more likely to reflect inflammation activation based on experience in recent studies.
Secondary
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
Time frame: Baseline, 4 weeks
Population: Biomarker evaluations were limited to IL-2 and IL-8 as those were thought more likely to reflect inflammation activation based on experience in recent studies.
Secondary
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.
Time frame: Baseline, 4 weeks
Population: Biomarker evaluations were limited to IL-2 and IL-8 as those were thought more likely to reflect inflammation activation based on experience in recent studies.
Secondary
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)
Time frame: Baseline, 4 weeks
Population: All participants randomized to each treatment were analyzed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Rivaroxaban | Change From Baseline to Week 4 in RF | 0.29 perfusion units |
| Placebo | Change From Baseline to Week 4 in RF | -0.62 perfusion units |
p-value: 0.4501Student t-test followed by ANOVA
Secondary
Change From Baseline to Week 4 in TAT
Assay for thrombin antithrombin (TAT) complexes performed using commercially available enzyme-linked immunosorbent assay (ELISA).
Time frame: Baseline, 4 weeks
Population: Data reported only for those participants who completed both interventions.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Rivaroxaban | Change From Baseline to Week 4 in TAT | -34.44 ug/mL |
| Placebo | Change From Baseline to Week 4 in TAT | 0.35 ug/mL |
p-value: 0.0767Student t-test followed by ANOVA
Secondary
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)
Time frame: Baseline, 4 weeks
Population: All participants randomized to each treatment were analyzed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Rivaroxaban | Change From Baseline to Week 4 in TH1 | 0.84 seconds |
| Placebo | Change From Baseline to Week 4 in TH1 | -0.51 seconds |
p-value: 0.4374Student t-test followed by ANOVA
Secondary
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
Time frame: Baseline, 4 weeks
Population: Data analyzed for the 13 participants completing both interventions but results for 6 participants in each group fell outside the standard curve and could not be extrapolated.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Rivaroxaban | Change From Baseline to Week 4 in the Plasma Marker of Inflammation IL-2 | -1.14 pg/mL |
| Placebo | Change From Baseline to Week 4 in the Plasma Marker of Inflammation IL-2 | 0.36 pg/mL |
p-value: 0.4442Student t-test followed by ANOVA
Secondary
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
Time frame: Baseline, 4 weeks
Population: Data analyzed for the 13 participants completing both interventions but results for 4 participants in the rivaroxaban group and 5 participants in the placebo group fell outside the standard curve and could not be extrapolated.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Rivaroxaban | Change From Baseline to Week 4 in the Plasma Marker of Inflammation IL-8 | 0.95 pg/mL |
| Placebo | Change From Baseline to Week 4 in the Plasma Marker of Inflammation IL-8 | -4.08 pg/mL |
p-value: 0.2545Student t-test followed by ANOVA
Secondary
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)
Time frame: Baseline, 4 weeks
Population: All participants randomized to each treatment were analyzed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Rivaroxaban | Change From Baseline to Week 4 in TM | -0.97 seconds |
| Placebo | Change From Baseline to Week 4 in TM | -2.01 seconds |
p-value: 0.347Student t-test followed by ANOVA
Secondary
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)
Time frame: Baseline, 4 weeks
Population: All participants randomized to each treatment were analyzed.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Rivaroxaban | Change in Ratio From Baseline to Week 4 in AH/AO | 0.05 ratio of AH to AO |
| Placebo | Change in Ratio From Baseline to Week 4 in AH/AO | -0.81 ratio of AH to AO |