Reduction in Hospitalizations, Sickle Cell Disease, Vaso-occlusive Crisis
Conditions
Keywords
Vaso-occlusive crisis, Reduction in hospitalizations, Sickle Cell Disease
Brief summary
In patients with SCD, the use of low dose anticoagulation as an outpatient may lead to a significant decrease in morbidity and as a result, decrease healthcare utilization and costs. This study attempts to critically avoid admissions by reducing daily pain scores and pain crisis as an outpatient by use of a novel oral anticoagulant.
Detailed description
There is not only significant morbidity associated with patients with SCD, but also costs associated with the numerous hospitalizations. Small studies have been unable to show clear benefit of the use of low dose anticoagulation in SCD due to limited sample size or the inclusion of very specific populations. However, studies have shown a decrease in the level of elevated prothrombotic markers with anticoagulation, and one study using full dose anticoagulation in patients with a generally milder form of SCD (with high protective hemoglobin) showed more rapid decrease in clinical pain with use of anticoagulation, suggesting a possible benefit of such therapy. Due to the paucity of data to support therapeutic dose LMWH in the more severe forms of SCD seen in the United States, we have chosen prophylactic dose anticoagulation. This study proposal attempts to critically avoid admissions by reducing daily pain scores and pain crisis as an outpatient by use of a novel oral anticoagulant. The development of novel anticoagulants such as oral direct factor Xa (FXa) inhibitors allows the realistic use of daily prophylactic dosing as an outpatient. Past studies as detailed earlier have been limited by attempts to use subcutaneous injections or frequent, close monitoring for acenocoumarol treatment, both which are not ideal for chronic daily use. Furthermore, the use of global assays such calibrated automated thrombography (CAT) have shown further details about thrombin generation in a population which is hypercoagulable at baseline. This is a double blind, parallel group, placebo controlled feasibility study with an enrollment target of 25 patients (12 per arm). All subjects that meet inclusion criteria as an outpatient, following a 1 month observation, will be randomized to receive an oral prophylactic dose factor Xa inhibitor (Apixaban 2.5mg po bid) or placebo for 6 months. Subjects will return for a 30 day (+/- 5 days) follow-up visit after the End of Treatment (EOT) visit. Initial randomization will occur by computerized randomization technique by the investigational drug services (IDS) at Duke University Medical Center.
Interventions
DRUGApixaban
Drug is taken by mouth twice a day for 6 months
DRUGPlacebo
Sponsors
Bristol-Myers Squibb
Nirmish Shah
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* documented HgbSS, SC or HgbS-beta0 thalassemia, * age ≥18 years old and ≤80, * seen in outpatient clinic ≥2 times in past year * seen for an acute care visit (hospitalization, emergency department, or day hospital visit) for pain \>2 times in the past year.
Exclusion criteria
* Hospitalization or day hospital visit for pain crisis within the past 2 weeks * Patients with ≥10 acute care visits within the past year will be excluded * Creatinine \>3.0 mg/dL * creatinine ≥1.5 mg/dL AND weight ≤60 kg * chronic use of antiplatelet or anticoagulation medication * Patients with known vasculopathy or Moya-Moya * platelet count \<100 X 109/L * AST or ALT \>3 times normal * chronic red blood cell transfusions (scheduled transfusions) * packed red blood cell transfusion within the past 2 months * Use of CYP3A4 and P-gp inhibitor medications
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pain as Measured by Visual Analog Scale (VAS) | Month 1 to Month 8 | The primary pain assessment tool will be a 10-cm horizontal visual analog scale (VAS), with 0 corresponding to no pain at one end and 10 indicating the worst pain at the other. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Thrombin Generation Using D-dimer Measurement as a Surrogate | Enrollment to 2 months | — |
| Daily Pain Scores While Hospitalized as Measured by VAS | up to 8 months | The primary pain assessment tool will be a 10-cm horizontal visual analog scale (VAS), with 0 corresponding to no pain at one end and 10 indicating the worst pain at the other. Secondary analysis will be performed to evaluate differences when patients are hospitalized and on study drug versus placebo. |
| Number of Hospitalizations During Treatment | up to 8 months | — |
Countries
United States
Participant flow
Recruitment details
Patients with sickle cell disease were enrolled as an outpatient in clinic while at baseline pain from January 2015 to September 2017.
Participants by arm
| Arm | Count |
|---|---|
| Apixaban Active drug Apixaban 2.5mg taken by mouth twice a day
Apixaban: Drug is taken by mouth twice a day for 6 months | 8 |
| Placebo Sugar pills that look like Apixaban that will be taken by mouth twice a day
Placebo | 8 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Apixaban | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 30 years STANDARD_DEVIATION 6.2 | 31.5 years STANDARD_DEVIATION 7.8 | 33 years STANDARD_DEVIATION 3.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 16 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 16 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 8 Participants | 16 Participants | 8 Participants |
| Sex: Female, Male Female | 5 Participants | 10 Participants | 5 Participants |
| Sex: Female, Male Male | 3 Participants | 6 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 8 |
| other Total, other adverse events | 2 / 8 | 0 / 8 |
| serious Total, serious adverse events | 2 / 8 | 0 / 8 |
Outcome results
Primary
Change in Pain as Measured by Visual Analog Scale (VAS)
The primary pain assessment tool will be a 10-cm horizontal visual analog scale (VAS), with 0 corresponding to no pain at one end and 10 indicating the worst pain at the other.
Time frame: Month 1 to Month 8
Population: Two participants in each group (Apixaban and Placebo) did not return for Month 8 visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Apixaban | Change in Pain as Measured by Visual Analog Scale (VAS) | -1 score on a scale | Standard Deviation 0.5 |
| Placebo | Change in Pain as Measured by Visual Analog Scale (VAS) | 0 score on a scale | Standard Deviation 0.4 |
p-value: 0.11t-test, 2 sided
Secondary
Change in Thrombin Generation Using D-dimer Measurement as a Surrogate
Time frame: Enrollment to 2 months
Population: Data not collected.
Secondary
Daily Pain Scores While Hospitalized as Measured by VAS
The primary pain assessment tool will be a 10-cm horizontal visual analog scale (VAS), with 0 corresponding to no pain at one end and 10 indicating the worst pain at the other. Secondary analysis will be performed to evaluate differences when patients are hospitalized and on study drug versus placebo.
Time frame: up to 8 months
Population: Two participants from each group (Apixaban and Placebo) did not return for Month 8 visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Apixaban | Daily Pain Scores While Hospitalized as Measured by VAS | 6.4 score on a scale | Standard Deviation 3.4 |
| Placebo | Daily Pain Scores While Hospitalized as Measured by VAS | 6.6 score on a scale | Standard Deviation 3.8 |
Secondary
Number of Hospitalizations During Treatment
Time frame: up to 8 months
Population: Two participants from each group (Apixaban and Placebo) did not return for 8 Month visit.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Apixaban | Number of Hospitalizations During Treatment | 3 hospitalizations | Standard Deviation 3.3 |
| Placebo | Number of Hospitalizations During Treatment | 1.5 hospitalizations | Standard Deviation 1.5 |