Conditions: Vaso-occlusive Crisis Reduction in Hospitalizations Sickle Cell Disease
Keywords: Vaso-occlusive crisis Reduction in hospitalizations Sickle Cell Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 16
Healthy volunteers: no

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.

Arms:
arm 1: Active drug Apixaban 2.5mg taken by mouth twice a day arm 2: Sugar pills that look like Apixaban that will be taken by mouth twice a day

Interventions: intervention 1: Apixaban intervention 2: Placebo
Intervention descriptions: intervention 1: Drug is taken by mouth twice a day for 6 months intervention 2: None

Protocol document:
Prot_SAP_000.pdf: 
 
Impact of Daily Prophylaxis Dose 
Anticoagulation with a Factor Xa Inhibitor 
(Apixaban) in Patients with Sickle Cell 
Disease  
 
 
 
Principal Investigator: Nirmish Shah MD 
 
 
 
 
 
 
 
A randomized trial to evaluate if prophylactic dose Apixaban not only reduces the known hypercoagulable 
state, but more importantly, has a salutary effect on clinical pain scores in patients with Sickle Cell Disease 
 
 
 
NCT02179177 
 
Document Date; October 4, 2016 
 
 
 
 


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TABLE OF CONTENTS 
 
1.0 INTRODUCTION AND BACKGROUND  
 
 
 
PAGE     4 
 
2.0 STUDY RATIONALE 
 
 
 
 
 
 
 
PAGE    4-5 
 
3.0 STUDY DESIGN  
 
 
 
 
 
 
 
PAGE    5-6 
3.1 SCREENING AND ELIGIBILITY 
 
 
 
 
 
 
 
  
4.0 SPECIFIC AIM 1  
 
 
 
 
 
 
 
PAGE    6-7 
4.1 STUDY PROCEDURES AIM 1 
4.2 DATA AND STATISTICAL ANALYSIS AIM 1 
 
5.0 SPECIFIC AIM 2  
 
 
 
 
 
 
 
PAGE    7-9 
5.1  STUDY PROCEDURES AIM 2 
5.2 DATA AND STATISTICAL ANALYSIS AIM 2 
 
6.0 STUDY VISIT PROCEDURES  
 
 
     
 
 
PAGE   9-11 
6.1   SCREENING/RANDOMIZATION VISIT 
6.1.2 OBSERVATIONAL PERIOD (30 DAYS 
6.1.3 MONTH 1 
6.1.4 MONTH 2, 4 AND 6 (telephone visits) 
6.1.5 MONTH 3 
6.1.6 MONTH 5 
6.1.7 MONTH 7 (End of Treatment) 
6.1.8 MONTH 9 (Follow-Up) 
 
7.0 STUDY DURATION 
 
 
 
 
 
 
 
PAGE      11 
 
8.0 DATA SAFETY AND MONITORING BOARD  
 
 
PAGE      11 
 
9.0 DATA SAFETY AND MONITORY PLAN  
 
 
 
PAGE   11-12   
9.1 ADVERSE EVENT REPORTING 
9.1.1 Collection of Safety Information 
9.1.2 Serious Adverse Events 
9.1.3 Non-serious Adverse Events 
 
 
9.2 ASSIGNMENT OF ADVERSE EVENT INTENSITY AND     PAGE   13 


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RELATIONSHIP TO INVESTIGATIONAL PRODUCT 
 
9.3 COLLECTION AND REPORTING  
 
 
 
PAGE 13-17 
9.3.1 Serious Adverse Events 
9.3.2 Handling of Expedited Safety Reports 
9.3.3 Non-serious Adverse Events 
9.3.4 Laboratory Test Abnormalities 
9.3.5 Overdose 
9.3.6 Pregnancy 
9.3.7 Potential Drug-Induced Liver Injury (DILI) 
9.3.8 Other Safety Considerations 
 
10.0  BIBLIOGRAPHY  
 
 
 
 
 
 
 
PAGE    18 
 
APPENDIX A 
 


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1.0 Introduction and Background 
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. Sickle cell disease (SCD) is most commonly 
affected by recurrent painful vaso-occlusive crisis (VOC) and although greater than 50% of patients with SCD 
have significant daily pain, only 5% of patients actually seek medical attention (Smith, 2008). Importantly, 
hospitalizations account for up to 90% of the medical care costs for patients with SCD (Yang, 1995). Review of 
data from the National Center for Health Statistics revealed the average direct costs per hospitalization (in 1996 
dollars) was estimated at $6300, for a total direct cost of $475 million per year. The use of anticoagulation in 
SCD builds upon recent studies including our own (Shah, 2012; Ataga, 2007; Francis, 1989; Stuart 2001) which 
document a hypercoagulable state and has been found to be promising in smaller past studies.  
 
Although few studies have attempted to evaluate clinical pain scores in the context of anticoagulation, several 
studies have examined the effects of anticoagulation on the coagulation system in SCD. Wolters et al 
documented that use of acenocoumarol at a mean INR of 1.64 resulted in a 50% decrease in plasma 
prothrombin fragment 1+2 in SCD patients during steady state. However, clinical evaluation was not performed 
in this initial small study (Wolters, 1995). Subsequently, Ahmed et al measured D-dimer in 37 sickle cell 
patients treated with low dose warfarin (mean dose of 1 mg) while in crisis. Their results revealed a significant 
decrease in D-dimer levels in patients treated with warfarin (Ahmed, 2004). These studies also documented no 
bleeding with low dose anticoagulation, along with the decrease in hypercoagulable markers.  
 
Studies evaluating the clinical benefit of anticoagulation in patients with SCD began with Chaplin et al, who 
revealed that long term use of daily prophylactic subcutaneous heparin in four SCD patients over several years 
(mean 8.7 years) was beneficial. Minimal improvement in clinical pain was reported in one, and moderate 
improvement in three. Results also included no bleeding and no thrombocytopenia. In addition, there was a 73% 
reduction in days of hospitalization per year and 74% reduction in hours spent in emergency rooms per year 
during heparin administration. Pretreatment pain patterns recurred when heparin was discontinued (Chaplin, 
1989). A larger study by Schnog et al examined 22 SCD patients in a double blind placebo controlled, cross-
over pilot study. This study used acenocoumarol dosed to achieve an INR of 1.6-2 and followed patients for a 
total of 23 weeks. Results included reduction in all hypercoagulable markers; however, there was no decrease in 
the number of hospitalizations. Limitations of this study arose from the small sample size and the large number 
of patients excluded (Schnog, 2001). Furthermore, subcutaneous heparin and warfarin may not be the optimal 
antithrombotic agents to use in this particular clinical setting. Thus, the inconclusive results from previous 
studies indicate that further investigations are needed to more effectively evaluate the role of low dose 
anticoagulation in SCD.  
 
2.0 Study Rationale 
 
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  
 
 
 
 


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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 are currently performing an inpatient study to evaluate if prophylactic 
dose LMWH not only reduces the known hypercoagulable state, but more importantly, has a salutary effect on  
clinical pain scores. 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. Our 
studies have revealed an increase in ‘thrombin burst’ and intrinsic hypercoagulability which can be monitored 
closely by CAT during treatment with a FXa inhibitor. 
 
There is evidence of the potential role of anticoagulants for reduction in this hypercoagulable state, and 
importantly reduction in clinical pain. Studies of anticoagulation in outpatients with SCD have included the use 
of LMWH and acenocoumarol. Both have difficulty in administration, monitoring and ultimately compliance. 
The development of direct factor Xa (FXa) inhibitors which are administered orally and require minimal 
monitoring is ideal for chronic administration. 
 
3.0 Study Design 
 
This is a double blind, parallel group, placebo controlled feasibility study (see figure 1) with an enrollment 
target of 60 patients (30 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. 
 
3.1 Screening and Eligibility 
 
All patients seen in our Adult Comprehensive Sickle Cell Center will be screened for eligibility. Currently, 
there are greater than 450 patients actively seen and an average of 60 patients seen per week. The same 
inclusion/exclusion criteria will be used for both arms of the study. 
 
Inclusion Criteria  
 
• documented HgbSS, SC or HgbS-beta0 thalassemia,  
• age ≥18 years old and ≤80, seen in outpatient clinic ≥2 times in past year, and  
• seen for an acute care visit (hospitalization, emergency department, or day hospital visit) for pain >2 
times in the past year. 
 
 


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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 
 
4.0 Specific Aim 1. Evaluate the impact of daily prophylactic dose anticoagulation (oral direct factor Xa 
inhibitor) on daily pain scores in outpatients with SCD. 
 
 
 
4.1 Study Procedures Aim 1 
Following randomization by IDS, and initial blood draw (Figure 1), patients will be given a daily pain 
logPatients will record daily pain scores and return in 1 month (+/- 5 days) at which time patients will then 
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. Along with the VAS, there will be novel 
methods of pain assessment that may prove to better measure the impact of pain in these patients.  One 
method is the use of the validated PROMIS format . PROMIS uses a 5-point Likert-type format with 
response options ranging from never to always. A total score is calculated by obtaining a sum of scores 
across items, with higher scores indicating greater impact of the particular domain to a patient’s daily living. 
Patients will have PRO performed on enrollment, after 1 month's use of study drug and at the end of 6 
months' use of study drug. Patients will complete PROMIS on a mobile device and have all results 


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recorded on the Duke secure server for further information. The second, a SMART application will be 
installed on patient’s iPhones/iPads at their request to assist with monitoring of symptoms. Patients without 
an Apple device can have one loaned to them until completion of the study.  
The devices will be returned to the study PI or coordinator per agreement at the time of enrollment.  Patients 
admitted to the hospital will continue their study drug or placebo unless deemed medically inappropriate by 
admitting physician. Patients upon discharge are to resume study drug per supervision of study  
 
 
principal investigator. Pain scores during hospitalization and for the subsequent 1 week will be recorded and 
used for secondary analysis of daily pain scores during crisis. 
 
Patients who during the course of the study have laboratory findings which reveal creatinine ≥1.5 mg/dL AND 
weight ≤60 kg; platelets < 100 X 109/L; or develop AST or ALT >3 times normal, will have study drug stopped 
and will be terminated from the study. 
 
Patients on hydroxyurea will be included in the study and sub-analysis will be performed to control for potential 
differences. All patients despite treatment with hydroxyurea will need to meet inclusion criteria of having 
clinically significant pain which requires >2 acute care visits. 
 
4.2 Data and Statistical Analysis Aim 1 
 
We power the study to test whether there is a significantly larger reduction in pain after administration of a 
daily prophylactic anticoagulation dose as compared to administration of a placebo.  A total of 60 patients will 
be randomly assigned to each drug arm. The primary endpoint is the mean pain score per patient over each of 
four time periods. The design has two sources of variation: the variation between the patients receiving the same 
drug and the variation due to the interaction of time by the patients within drug arm. It is of interest to test 
whether the change in the pain score over the four time periods differs between the prophylactic anticoagulation 
dose arm and the placebo arm. From the literature the standard deviation of the mean pain score per patient is 
1.5. Assume the true mean pain scores over the four time periods for the placebo and prophylactic 
anticoagulation dose arms are 3.9, 3.9, 3.9, 3.9 and 3.9, 3.12, 3.12, 3.12, respectively. Then, a total of 60 
patients randomized equally to each drug arm will detect the difference in the change between the two arms in 
the mean pain scores over time, as specified by the preceding mean pain scores, with a power of at least 0.836 
for a one-sided 0.05 test. Anticipating that 20% (10 patients) may have incomplete data (less than 75% of daily 
pain scores recorded or missing more than one dose of study drug per week), may be lost to follow up, or may 
drop out; we have also found a power of at least 78.4% for 50 patients. 
 
We expect two positive effects from prophylactic doses of apixaban on the patient reported outcomes: 
• 
PROs assessing fatigue, physical function, and pain impact will improve in patients administered daily 
prophylactic dose apixaban compared to placebo. 
• 
We believe that there will be a significant correlation between PROs and pain scores. 
 
 
Statistical Analysis 
The primary outcome of interest is to test the effect on the mean daily pain score due to the arm by time 
interaction. Secondary outcome will include comparison of daily pain scores while hospitalized between 
treatment arms and the number of hospitalizations during each treatment period. 


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All analyses will be performed using SAS version 9 or greater (SAS Institute Inc., Cary, NC). Data will be 
analyzed using descriptive statistics including mean and standard deviation. Comparisons are to be performed 
using SAS’s PROC GLM with a model that accounts for all fixed and random effects in the design. 
 
5.0 Specific Aim 2: Determine the effect of prophylactic dose anticoagulation on markers of thrombin 
generation during outpatient steady state as well as inpatient VOC. 
 
As described in section 3.0, we will perform a double blind, parallel group, placebo controlled feasibility study 
with an enrollment target of 60 patients (30 per arm). 
 
5.1 Study Procedures Aim 2 
 
As described earlier (Figure 1), patients begin a 1 month observation following randomization. Patients will 
have blood drawn on enrollment and when they return in 1 month (+/- 5 days) to begin study drug. Subsequent 
blood draws performed at 2 month intervals while on study drug. Blood draws will occur between 2 and 4 hours  
from previous dose taken and ± 5 days regardless of hospitalization. Patients will be called monthly between in 
person visits to assess for AE/SAE and to reinforce the importance of medication compliance. Graded 
incentives may be given monthly to encourage patients to continue on study and return for follow up blood 
draws.  
 
 
Platelet poor plasma will be separated and stored to allow batch testing for hypercoagulable markers and 
markers of inflammation. Markers of thrombin generation will include D-dimer, thrombin-antithrombin (TAT) 
complex, and CAT. Both D-dimer and TAT will be performed using enzyme-linked immunosorbent assay 
(ELISA). CAT will be performed using the Fluoroskan Ascent plate reader (TCoag) and phases to be analyzed  
include lag phase, slope, peak and endogenous thrombin potential. Markers of inflammation will also be 
measured at each of these time points (IL-6 and sVCAM) which are performed by ELISA. 
 
Patients admitted to the hospital will continue their study drug or placebo unless deemed medically 
inappropriate by admitting physician. Patients upon discharge are to resume study drug per supervision of study 
principal investigator. Blood will be drawn for secondary analysis for hypercoaguability on any inpatient 
hospitalizations on day 1, 3 and 5 but will not be included in primary analysis.  
 
5.2 Data and Statistical Analysis 
Sample Size 
The same design used in Aim 1 applies to Aim 2. We analyze the change in thrombin generation from 
enrollment to 2 months following initiation of study drug. We hypothesize that the anticoagulation drug will 


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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.  
 
No studies to date have evaluated the influence of anticoagulants on thrombin generation as measured by CAT, 
therefore sample size and expected differences are calculated based on available studies examining D-dimer.   
 
 
Statistical Analysis 
For our primary outcome, we will compare mean changes in thrombin generation (D-dimer, TAT and phases of 
CAT) for patients treated with prophylactic dose anticoagulation and placebo. Secondary outcomes will include 
correlation of hypercoagulable and inflammatory markers to clinical outcomes (such as pain, hospitalization, 
and number of acute care visits).  
 
In addition, we expect that 50% of the patients to be hospitalized and continue their medication (placebo or 
drug) as assigned at randomization. For these patients, thrombin generation D-dimer measures will be collected  
at admission, 3 days and 5 days. Therefore, as a secondary aim, for these hospitalized patients we will analyze 
the difference between the placebo and drug groups in the change over time in the mean D-dimer values.  
 
Planned Analysis of Primary Endpoint  
Following the enrollment of the 60 patients, and completion of the 7 month study period for each patient, all 
data will be subsequently analysed with the assistance of the Duke Translational Medical Institute. Barry 
Moser, PhD is our lead stastician who will continue to provide statistical support and analysis through this 
study. 
 
Primary analysis of daily pain scores will be performed for patients on treatment with Apixaban and compared 
to patients on placebo, to determine if treatment decreases daily pain scores. In addition, we will compare 
changes in thrombin generation from enrollment to 2 months for patients treated with Apixaban versus placebo. 
 
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. 
 
6.0 Study Visit Procedures (See Appendix A) 
 
6.1 Screening/Randomization Visit 
 The investigator or designee will:  
o Obtain written informed consent 
o Obtain relevant medical history 
o Determine eligibility 
o Conduct pregnancy test (WOCBP only) 
o Obtain blood samples for research laboratory tests 
 Research labs include: D-dimer, thrombin-antithrombin, and calibrated automated 
thrombography, IL-6, sVCAM 
o Assess concomitant medication use  


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o Randomize subject  
o Perform Pain Score 
o Distribute Pain log 
o Perform Patient Reported Outcome Computerized Questionnaire (PROMIS) 
o Install SMART app on subject’s phone or provide subject with a device 
 
6.1.2 Observational Period (30 days)  
Via a telephone contact at 2 weeks, the investigator or designee will:  
o Assess concomitant medication use 
o Review pain log completion guidelines 
o Assess adverse events 
 
 
6.1.3 Month 1 
The investigator or designee will:  
o Obtain blood samples for research laboratory tests 
 Research labs include: D-dimer, thrombin-antithrombin, and calibrated automated 
thrombography. 
o Assess concomitant medication use  
o Perform Pain Score 
o Dispense study drug 
o Assess pain log completion compliance 
o Assess adverse events 
 
6.1.4 Month 1, 2, 3, 4, 5, 6, 7 and 8 (telephone) – 2 weeks following last clinic visit 
Via a telephone contact, the investigator or designee will:  
o Assess concomitant medication use 
o Review pain log completion guidelines 
o Assess adverse events 
 
6.1.5 Month 2 
The investigator or designee will:  
o Assess concomitant medication use  
o Perform Pain Score 
o Dispense study drug 
o Assess pain log completion compliance 
o Assess adverse events 
o Perform Patient Reported Outcome Computerized Questionnaire (PROMIS) 
 
6.1.6 Month 3  
The investigator or designee will:  
o Obtain blood samples for research laboratory tests 
 Research labs include: D-dimer, thrombin-antithrombin, and calibrated automated 
thrombography. 
o Assess concomitant medication use  
o Perform Pain Score 
o Assess study drug compliance 


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o Dispense study drug 
o Assess pain log completion compliance 
o Assess adverse events 
 
6.1.7 Month 4  
The investigator or designee will:  
o Assess concomitant medication use  
o Perform Pain Score 
o Assess study drug compliance 
o Dispense study drug 
o Assess pain log completion compliance 
o Assess adverse events 
 
 
6.1.8 Month 5 
The investigator or designee will:  
o Obtain blood samples for research laboratory tests 
 Research labs include: D-dimer, thrombin-antithrombin, and calibrated automated 
thrombography, IL-6, and sVCAM. 
o Assess concomitant medication use  
o Perform Pain Score 
o Assess study drug compliance 
o Dispense study drug 
o Assess pain log completion compliance 
o Assess adverse events 
 
6.1.9 Month 6  
The investigator or designee will:  
o Assess concomitant medication use  
o Perform Pain Score 
o Assess study drug compliance 
o Dispense study drug 
o Assess pain log completion compliance 
o Assess adverse events 
 
6.1.10 Month 7 (End of Treatment) 
The investigator or designee will:  
o Assess concomitant medication use  
o Perform Pain Score 
o Assess study drug compliance 
o Assess pain log completion compliance 
o Assess adverse events 
o Perform Patient Reported Outcome Computerized Questionnaire (PROMIS) 
 
6.1.11 Month 8 (Follow-Up) 
The investigator or designee will:  
o Obtain blood samples for research laboratory tests 


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 Research labs include: D-dimer, thrombin-antithrombin, and calibrated automated 
thrombography. 
o Assess concomitant medication use  
o Perform Pain Score 
o Assess pain log completion compliance 
o Assess adverse events 
 
7.0 Study Duration 
Enrollment for this study will be completed within the first 12 months (average 5 patients per month), followed 
by 8 months to allow completion of study by all patients. 
 
 
8.0 Data and Safety Monitoring Board.  
The Duke University Data and Safety Monitoring Board (DSMB) is a Committee that has been established for 
the purpose of monitoring clinical studies. The DSMB has multiple responsibilities including: 
• Assessing risk and complexity of those clinical trials that have been submitted for review 
• Determining the appropriate level of data and safety monitoring 
• Reviewing the reports of all serious adverse events (SAEs) that have been experienced by participants in 
those active clinical trials that are being monitored by the DSMB 
• Reviewing the regularly submitted (usually at least yearly) data and safety monitoring reports that are 
required of all active clinical trials.   
• Recommending appropriate actions (closure, increased monitoring, etc.) to the Principal Investigator. 
 
9.0 Data Safety and Monitoring Plan 
We will be using the descriptive terminology developed by the National Cancer Institute for use in reporting 
adverse events: Common Toxicology Criteria for Adverse Events (CTCAE) version 4.0, dated May 29, 2009. 
The website for the CTCAE is http://evs.nci.nih.gov/ftp1/CTCAE/About.html. The CTCAE includes a grading 
(severity) scale for each adverse event term. 
 
9.1 
Adverse Event Reporting 
 
9.1.1 Collection of Safety Information 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing 
medical condition in a patient or clinical investigation subject administered an investigational (medicinal)  
 
product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of investigational product, whether or not considered related to the 
investigational product. 
 
Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a subject. (In order to prevent reporting bias, subjects should not be questioned regarding the 
specific occurrence of one or more AEs.) 
 


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9.1.2 Serious Adverse Events 
A serious AE (SAE) is any untoward medical occurrence that at any dose:  
• results in death 
• is life-threatening (defined as an event in which the subject was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it were more severe) 
• requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE below)      
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect  
• is an important medical event (defined as a medical event(s) that may not be immediately life-threatening or 
result in death or hospitalization but, based upon appropriate medical and scientific judgment, may 
jeopardize the subject or may require intervention [e.g., medical, surgical] to prevent one of the other 
serious outcomes listed in the definition above.) Examples of such events include, but are not limited to, 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization.)   
• Suspected transmission of an infectious agent (e.g., any organism, virus or infectious particle, pathogenic or 
non-pathogenic) via the study drug is an SAE. 
Although pregnancy, overdose, cancer are not always serious by regulatory definition, these events must be 
handled as SAEs.  (See Section 9.3.6 for reporting pregnancies.) 
 
NOTE: The following hospitalizations are not considered SAEs in BMS clinical studies: 
• a visit to the emergency room or other hospital department lasting less than 24 hours that does not result 
in admission (unless considered an “important medical event” or a life-threatening event) 
• elective surgery planned before signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of health status (e.g., routine 
colonoscopy) 
• medical/surgical admission for purpose other than remedying ill health state that was planned before 
study entry. Appropriate documentation is required in these cases. 
• Admission encountered for another life circumstance that carries no bearing on health status and 
requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, caregiver respite, 
family circumstances, administrative). 
 
9.1.3 Nonserious Adverse Events 
A nonserious adverse event is an AE not classified as serious. 
9.2 Assignment of Adverse Event Intensity and Relationship to Investigational Product 
The following categories and definitions of causal relationship to investigational product as determined by a 
physician should be used: 
 
Related: There is a reasonable causal relationship to investigational product administration and the adverse 
event. 


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Not Related: There is not a reasonable causal relationship to investigational product administration and the 
adverse event. 
 
The expression “reasonable causal relationship” is meant to convey in general that there are facts (e.g., evidence 
such as de-challenge/re-challenge) or other arguments to suggest a positive causal relationship. 
9.3 Collection and Reporting 
Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a subject. (In order to prevent reporting bias, subjects should not be questioned regarding the 
specific occurrence of one or more AEs.) 
 
If known, the diagnosis of the underlying illness or disorder should be recorded, rather than its individual 
symptoms. The following information should be captured for all AEs: onset, duration, intensity, seriousness, 
relationship to investigational product, action taken, and treatment required. If treatment for the AE was 
administered, it should be recorded in the medical record. 
The investigator shall supply the sponsor and Ethics Committee with any additional requested information, 
notably for reported deaths of subjects. 
 
All AE/SAEs will be reported to the DSMB and BMS. The DSMB will review these data at their regular 
meeting and notify the Principal Investigator if safety appears to be an issue. After 12 months of this study (or 
completion of 20 patients, whichever comes first), all of the safety data, including information on any deaths, 
will be presented to the DSMB in a tabular format. The investigators will also prepare an overall report to 
accompany the tables. The DSMB will review the report and determine if there is a safety concern. If there are 
significant adverse events, the DSMB may recommend that the study be terminated. All AE/SAEs will be 
included in the final study report. 
 
 
9.3.1 Serious Adverse Events 
Following the subject’s written consent to participate in the study, all SAEs must be collected, including those 
thought to be associated with protocol-specified procedures. All SAEs must be collected that occur within 70 
days of discontinuation of dosing of the investigational product. If applicable, SAEs must be collected that 
relate to any later protocol-specified procedure (e.g., a follow-up skin biopsy). The investigator should notify 
BMS of any SAE occurring after this time period that is believed to be related to the investigational product or 
protocol-specified procedure. 
 
All SAEs whether related or unrelated to the study drug, apixaban, must be immediately reported to BMS (by 
the investigator or designee) within 24 hours of becoming aware of the event. If only limited information is 
initially available, follow-up reports are required. The original SAE form must be kept on file at the study site. 
 
All SAEs should be faxed or emailed to BMS at: 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 


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Serious adverse events, whether related or unrelated to investigational product, must be recorded on the SAE 
page and reported expeditiously to BMS (or designee) to comply with regulatory requirements. An SAE report 
should be completed for any event where doubt exists regarding its status of seriousness.  
 
All SAEs must be immediately reported by confirmed facsimile transmission (fax) and mailing of the 
completed SAE page. In some instances where a facsimile machine is not available, overnight express mail may 
be used. If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE 
reports should include the same investigator term(s) initially reported.) In selected circumstances, the protocol 
may specify conditions that require additional telephone reporting.  
 
If the investigator believes that an SAE is not related to the investigational product, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy, or a complication of a study procedure), the 
relationship should be specified in the narrative section of the SAE page. 
 
If an ongoing SAE changes in its intensity or relationship to the investigational product, a follow-up SAE report 
should be sent immediately to the sponsor. As follow-up information becomes available it should be sent 
immediately using the same procedure used for transmitting the initial SAE report. All SAEs should be 
followed to resolution or stabilization. 
9.3.2 Handling of Expedited Safety Reports 
In accordance with local regulations, BMS will notify investigators of all SAEs that are suspected (related to the 
investigational product) and unexpected (i.e., not previously described in the Investigator Brochure). In the 
European Union (EU), an event meeting these criteria is termed a Suspected, Unexpected Serious Adverse 
Reaction (SUSAR). investigator notification of these events will be in the form of an expedited safety report 
(ESR).  
 
Other important findings which may be reported by the sponsor as an ESR include: increased frequency of a 
clinically significant expected SAE, an SAE considered associated with study procedures that could modify the 
conduct of the study, lack of efficacy that poses significant hazard to study subjects, clinically significant safety  
finding from a nonclinical (e.g., animal) study, important safety recommendations from a study data monitoring 
committee, or sponsor decision to end or temporarily halt a clinical study for safety reasons. 
 
Upon receiving an ESR from BMS, the investigator must review and retain the ESR with the Investigator 
Brochure. Where required by local regulations or when there is a central IRB/IEC for the study, the sponsor will 
submit the ESR to the appropriate IRB/IEC. The investigator and IRB/IEC will determine if the informed 
consent requires revision. The investigator should also comply with the IRB/IEC procedures for reporting any 
other safety information.  
 
In addition, suspected serious adverse reactions (whether expected or unexpected) shall be reported by BMS to 
the relevant competent health authorities in all concerned countries according to local regulations (either as 
expedited and/or in aggregate reports). 
 


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9.3.3 Nonserious Adverse Events 
The collection of nonserious AE information should begin at initiation of investigational product. Nonserious 
AE information should also be collected from the start of a placebo lead-in period or other observational period 
intended to establish a baseline status for the subjects.  
 
If an ongoing nonserious AE worsens in its intensity, or if its relationship to the investigational product 
changes, a new nonserious AE entry for the event should be completed. Nonserious AEs should be followed to 
resolution or stabilization, or reported as SAEs if they become serious. Follow-up is also required for 
nonserious AEs that cause interruption or discontinuation of investigational product, or those that are present at 
the end of study participation. Subjects with nonserious AEs at study completion should receive post-treatment 
follow-up as appropriate. 
 
All identified nonserious AEs must be recorded and described in the medical record. 
9.3.4 Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following institutional procedures. 
Test results that constitute SAEs should be documented and reported as such. 
The following laboratory abnormalities should be documented and reported appropriately: 
 
• any laboratory test result that is clinically significant or meets the definition of an SAE 
• any laboratory abnormality that required the subject to have study drug discontinued or interrupted 
• any laboratory abnormality that required the subject to receive specific corrective therapy. 
9.3.5 Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product that is considered 
both excessive and medically important. All occurrences of overdose must be reported as an SAE. 
9.3.6 Pregnancy 
Sexually active WOCBP must use an effective method of birth control during the course of the study, in a 
manner such that risk of failure is minimized. Before enrolling WOCBP in this clinical study, the investigator 
must review the guideline about study participation for WOCBP which can be found in the GCP Manual for 
Investigators. The topics include the following: 
 
• General Information 
• Informed Consent Form 
• Pregnancy Prevention Information Sheet 
 
• Drug Interactions with Hormonal Contraceptives 
• Contraceptives in Current Use 
• Guidelines for the Follow-up of a Reported Pregnancy. 
 
Before study enrollment, WOCBP must be advised of the importance of avoiding pregnancy during study 
participation and the potential risk factors for an unintentional pregnancy. The subject must sign an informed 
consent form documenting this discussion. 


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All WOCBP MUST have a negative pregnancy test within 72 hours before receiving apixaban. The 
minimum sensitivity of the pregnancy test must be 25 IU/L or equivalent units of HCG. If the pregnancy test is 
positive, the subject must not receive apixaban and must not be enrolled in the study. 
 
In addition, all WOCBP should be instructed to contact the investigator immediately if they suspect they 
might be pregnant (e.g., missed or late menstrual period) at any time during study participation. 
If, following initiation of the investigational product, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of investigational product exposure, including during at least 6 
half-lives after product administration, the investigational product will be permanently discontinued in an 
appropriate manner (e.g., dose tapering if necessary for subject safety). The investigator must immediately 
notify BMS of this event and record the pregnancy on the Pregnancy Surveillance Form (not an SAE form). 
Initial information on a pregnancy must be reported immediately to BMS, and the outcome information 
provided once the outcome is known. Completed Pregnancy Surveillance Forms must be forwarded to BMS 
according to SAE reporting procedures. 
 
Any pregnancy that occurs in a female study participant or a female partner of a male study participant should 
be reported to the sponsor. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 
Protocol-required procedures for study discontinuation and follow-up must be performed on the subject unless 
contraindicated by pregnancy (e.g., x-ray studies). Other appropriate pregnancy follow-up procedures should be 
considered if indicated. The study staff will continue to follow the pregnant female throughout the course of the 
pregnancy until an outcome is known. In addition, the investigator must report to BMS and follow-up on 
information regarding the course of the pregnancy, including perinatal and neonatal outcome. Infants should be 
followed for a minimum of 8 weeks. 
 
The study staff will continue to follow you throughout the course of the pregnancy, including perinatal and 
neonatal until an outcome is known. The study staff will collect information for your infant(s) from the medical 
chart and through phone contact with the parent/parents. The information will include any complications or 
abnormalities at birth.  The study staff will also document the following information: date of birth, sex, birth 
weight, head circumference and Apgar score (Appearance, Pulse, Grimace, Activity, Respiration).  The study 
staff will continue to collect information about your infant for a minimum of 8 weeks after birth. 
 
 
 
9.3.7 Adverse Events of Special Interest  
Wherever possible, timely confirmation of initial liver-related laboratory abnormalities should occur prior to the 
reporting of a potential adverse event (AE) of special interest. All occurrences of potential adverse event of 
special interest, meeting the defined criteria, must be reported as SAEs (see Section 7.2.1 for reporting details). 
 
In this study, the following adverse events are to be reported to BMS, regardless of whether these reports are 
classified as serious or unexpected: 
•             Potential or suspected cases of liver injury including but not limited to liver test abnormalities, 
jaundice, hepatitis or cholestasis.. 


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SAE Reconciliation 
The investigator will reconcile the clinical database SAE cases transmitted to BMS Global Pharmacovigilance 
(GPV&E). Reconciliation will occur every three months and once just prior to database lock/Final 
Study Report (FSR).  The investigator will request a safety data reconciliation report to 
aepbusinessprocess@bms.com.  BMS GPV&E will e-mail upon request from the investigator, the 
GPV&E reconciliation report. The data elements listed on the GPV&E safety data reconciliation 
report will be used for case identification purposes. If the investigator determines a case was not 
transmitted to BMS GPV&E, the case will be sent immediately. 
9.3.8  Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, x-rays, and 
any other potential safety assessments, whether or not these procedures are required by the protocol, should also 
be recorded in the medical record. 
 
 
 
 
 
 
 
 
 
 
 
 
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