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Apixaban in Patients With Sickle Cell Disease

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ClinicalTrials.gov Identifier: NCT02179177
Recruitment Status : Terminated (funding has been exhausted)
First Posted : July 1, 2014
Last Update Posted : April 22, 2019
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
Nirmish Shah, Duke University

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.

Condition or disease Intervention/treatment Phase
Vaso-occlusive Crisis Reduction in Hospitalizations Sickle Cell Disease Drug: Apixaban Drug: Placebo Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 16 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: Impact of Daily Prophylaxis Dose Anticoagulation With a Factor Xa Inhibitor (Apixaban) in Patients With Sickle Cell Disease
Study Start Date : January 2015
Actual Primary Completion Date : September 3, 2017
Actual Study Completion Date : September 3, 2017

Resource links provided by the National Library of Medicine

Drug Information available for: Apixaban

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



Primary Outcome Measures :
  1. Mean daily pain score in outpatients with SCD [ Time Frame: 6 months ]
    After randomization and initial blood draw,patients will be given a daily pain log. Patients record daily pain scores and return in 1 month (+/- 5 days) at which time patients will be given a 1 month supply of study drug. Patients will return monthly (+/- 5 days) to return daily pain logs, verify compliance to medication, review completion of daily pain logs, and give additional study drug for the next month. Patients must adhere to daily administration of study drug and miss no more than 2 doses per week. Clinical pain scores will also be performed with each visit. 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. The daily pain log will include the VAS and if the patient classifies their pain as 'crisis' or not. Patients will be called monthly between in person visits to assess for AE/SAE and to reinforce the importance of medication compliance.


Secondary Outcome Measures :
  1. Change in thrombin generation from enrollment to 2 months following initiation of study drug. [ Time Frame: Enrollment to 2 months ]
    The investigator will analyze the change in thrombin generation from enrollment to 2 months following initiation of study drug. The investigator hypothesizes that the anticoagulation drug will cause a decrease in thrombin generation from baseline to two months. From the literature the standard deviation of the D-dimer measure per patient is 500. With a total of 60 patients randomized equally to each drug sequence, and conservatively assuming no correlation between D-dimer values from baseline to 2 months on the same patient, we achieve a power of 0.863 to detect a mean D-dimer difference in the change from baseline to 2 months between the placebo and the daily prophylactic anticoagulation dose groups of 250 mg/l {= [(1000-750) - (1000-1000)] mg/l} for a one-sided 0.05 test.

  2. Comparison of daily pain scores while hospitalized between treatment arms [ Time Frame: 6 months ]
    Secondary analysis will be performed to evaluate differences when patients are hospitalized and on study drug versus placebo, as well as healthcare utilization for patients treated with Apixaban.

  3. Number of hospitalizations during each treatment period. [ Time Frame: 6 months ]
    Secondary analysis will be performed to evaluate differences when patients are hospitalized and on study drug versus placebo, as well as healthcare utilization for patients treated with Apixaban.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02179177


Locations
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United States, North Carolina
Duke University Medical Center
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
Nirmish Shah
Bristol-Myers Squibb
Investigators
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Principal Investigator: Nirmish Shah, MD Duke University

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Responsible Party: Nirmish Shah, Assistant Professor, Duke University
ClinicalTrials.gov Identifier: NCT02179177     History of Changes
Other Study ID Numbers: Pro00048953
First Posted: July 1, 2014    Key Record Dates
Last Update Posted: April 22, 2019
Last Verified: April 2019
Keywords provided by Nirmish Shah, Duke University:
Vaso-occlusive crisis
Reduction in hospitalizations
Sickle Cell Disease
Additional relevant MeSH terms:
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Anemia, Sickle Cell
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Apixaban
Factor Xa Inhibitors
Antithrombins
Serine Proteinase Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Anticoagulants