Apixaban in Patients With Sickle Cell Disease

Impact of Daily Prophylaxis Dose Anticoagulation With a Factor Xa Inhibitor (Apixaban) in Patients With Sickle Cell Disease

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.

Study Overview

• Status: Terminated
• Conditions: Sickle Cell Disease; Vaso-occlusive Crisis; Reduction in Hospitalizations
• Intervention / Treatment: Drug: Placebo; Drug: Apixaban

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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Apixaban; Active drug Apixaban 2.5mg taken by mouth twice a day	Drug: Apixaban; Drug is taken by mouth twice a day for 6 months
Placebo Comparator: Placebo; Sugar pills that look like Apixaban that will be taken by mouth twice a day	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Month 1 to Month 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Thrombin Generation Using D-dimer Measurement as a Surrogate		Enrollment to 2 months
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.	up to 8 months
Number of Hospitalizations During Treatment		up to 8 months

Collaborators and Investigators

• Sponsor: Nirmish Shah
• Collaborators: Bristol-Myers Squibb

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): September 3, 2017
• Study Completion (Actual): September 3, 2017

Study Registration Dates

• First Submitted: June 27, 2014
• First Submitted That Met QC Criteria: June 27, 2014
• First Posted (Estimate): July 1, 2014

Study Record Updates

• Last Update Posted (Actual): March 11, 2020
• Last Update Submitted That Met QC Criteria: February 27, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: Sickle Cell Disease; Vaso-occlusive crisis; Reduction in hospitalizations
• Additional Relevant MeSH Terms: Hematologic Diseases; Genetic Diseases, Inborn; Anemia; Anemia, Hemolytic, Congenital; Anemia, Hemolytic; Hemoglobinopathies; Anemia, Sickle Cell; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Apixaban
• Other Study ID Numbers: Pro00048953