Apixaban in Patients With Sickle Cell Disease

• Sponsor: Nirmish Shah (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02179177
• Collaborator: Bristol-Myers Squibb (Industry)
• Enrollment: 16
• Location: 1
• Arms: 2
• Duration (Months): 32.1
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Study Design

• Study Type: Interventional
• 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: Jan 1, 2015
• Actual Primary Completion Date: Sep 3, 2017
• Actual Study Completion Date: Sep 3, 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Change in Thrombin Generation Using D-dimer Measurement as a Surrogate [Enrollment to 2 months]

2. 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.

3. Number of Hospitalizations During Treatment [up to 8 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Nirmish Shah
• Bristol-Myers Squibb

Investigators

• Principal Investigator: Nirmish Shah, MD, Duke University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 4, 2016

More Information

Publications

None provided.

• Responsible Party: Nirmish Shah, Assistant Professor, Duke University
• ClinicalTrials.gov Identifier: NCT02179177
• Other Study ID Numbers: Pro00048953
• First Posted: Jul 1, 2014
• Last Update Posted: Mar 11, 2020
• Last Verified: Feb 1, 2020

• Keywords provided by Nirmish Shah, Assistant Professor, Duke University: Vaso-occlusive crisis; Reduction in hospitalizations; Sickle Cell Disease
• Additional relevant MeSH terms: Anemia, Sickle Cell; Apixaban

Study Results

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.

Arm/Group Title	Apixaban	Placebo
Arm/Group Description	Active drug Apixaban 2.5mg taken by mouth twice a day Apixaban: Drug is taken by mouth twice a day for 6 months	Sugar pills that look like Apixaban that will be taken by mouth twice a day Placebo
Period Title: Overall Study
STARTED	8	8
COMPLETED	6	6
NOT COMPLETED	2	2

Baseline Characteristics

Arm/Group Title	Apixaban	Placebo	Total
Arm/Group Description	Active drug Apixaban 2.5mg taken by mouth twice a day Apixaban: Drug is taken by mouth twice a day for 6 months	Sugar pills that look like Apixaban that will be taken by mouth twice a day Placebo	Total of all reporting groups
Overall Participants	8	8	16
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	30 (6.2)	33 (3.9)	31.5 (7.8)
Sex: Female, Male (Count of Participants)
Female	5 62.5%	5 62.5%	10 62.5%
Male	3 37.5%	3 37.5%	6 37.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%
Not Hispanic or Latino	0 0%	0 0%	0 0%
Unknown or Not Reported	8 100%	8 100%	16 100%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	8 100%	8 100%	16 100%
White	0 0%	0 0%	0 0%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	8 100%	8 100%	16 100%

Outcome Measures

1. Primary Outcome

Title	Change in Pain as Measured by Visual Analog Scale (VAS)
Description	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

Outcome Measure Data

Analysis Population Description

Two participants in each group (Apixaban and Placebo) did not return for Month 8 visit.

Arm/Group Title	Apixaban	Placebo
Arm/Group Description	Active drug Apixaban 2.5mg taken by mouth twice a day Apixaban: Drug is taken by mouth twice a day for 6 months	Sugar pills that look like Apixaban that will be taken by mouth twice a day Placebo
Measure Participants	6	6
Mean (Standard Deviation) [score on a scale]	-1 (0.5)	0 (0.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Apixaban, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.11
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Thrombin Generation Using D-dimer Measurement as a Surrogate
Time Frame	Enrollment to 2 months

Outcome Measure Data

Analysis Population Description

Data not collected.

Arm/Group Title	Apixaban	Placebo
Arm/Group Description	Active drug Apixaban 2.5mg taken by mouth twice a day Apixaban: Drug is taken by mouth twice a day for 6 months	Sugar pills that look like Apixaban that will be taken by mouth twice a day Placebo
Measure Participants	0	0

3. Secondary Outcome

Title	Daily Pain Scores While Hospitalized as Measured by VAS
Description	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

Outcome Measure Data

Analysis Population Description

Two participants from each group (Apixaban and Placebo) did not return for Month 8 visit.

Arm/Group Title	Apixaban	Placebo
Arm/Group Description	Active drug Apixaban 2.5mg taken by mouth twice a day Apixaban: Drug is taken by mouth twice a day for 6 months	Sugar pills that look like Apixaban that will be taken by mouth twice a day Placebo
Measure Participants	6	6
Mean (Standard Deviation) [score on a scale]	6.4 (3.4)	6.6 (3.8)

4. Secondary Outcome

Title	Number of Hospitalizations During Treatment
Time Frame	up to 8 months

Outcome Measure Data

Analysis Population Description

Two participants from each group (Apixaban and Placebo) did not return for 8 Month visit.

Arm/Group Title	Apixaban	Placebo
Arm/Group Description	Active drug Apixaban 2.5mg taken by mouth twice a day Apixaban: Drug is taken by mouth twice a day for 6 months	Sugar pills that look like Apixaban that will be taken by mouth twice a day Placebo
Measure Participants	6	6
Mean (Standard Deviation) [hospitalizations]	3 (3.3)	1.5 (1.5)

Adverse Events

Time Frame	8 months
Arm/Group Title	Apixaban		Placebo
Arm/Group Description	Active drug Apixaban 2.5mg taken by mouth twice a day Apixaban: Drug is taken by mouth twice a day for 6 months		Sugar pills that look like Apixaban that will be taken by mouth twice a day Placebo
All Cause Mortality
	Apixaban		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)
Serious Adverse Events
	Apixaban		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/8 (25%)		0/8 (0%)
Pregnancy, puerperium and perinatal conditions
Pregnancy	1/8 (12.5%)		0/8 (0%)
Surgical and medical procedures
Hospitalization	1/8 (12.5%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Apixaban		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/8 (25%)		0/8 (0%)
Cardiac disorders
Sickle Cell Crisis	1/8 (12.5%)		0/8 (0%)
Musculoskeletal and connective tissue disorders
Sickle Cell Crisis	1/8 (12.5%)		0/8 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.