Clinical trial NCT03594045
Conditions: Heparin-induced Thrombocytopenia Heparin-induced Thrombocytopenia and Thrombosis
Keywords: Heparin-induced Thrombocytopenia
Sponsor: Massachusetts General Hospital
Start date: 2018-12-18; Completion date: 2019-10-30
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This research study is studying a drug as a possible treatment for heparin induced thrombocytopenia (HIT) or Heparin-induced Thrombocytopenia and Thrombosis (HITT).

The drug involved in this study is apixaban.

Detailed description:
This research study is a Phase II clinical trial.

The FDA (the U.S. Food and Drug Administration) has not approved apixaban as a treatment option for this specific disease but it has been approved for other uses.

HIT and HITT are common and severe complications of heparin therapy. Once patients are diagnosed with either one of these, they are typically switched to a non-heparin anticoagulant (a type of drug that thins your blood). As of now the only drug that is FDA approved for HIT or HITT is argatroban, which is administered continuously through an IV over multiple days and is extremely costly.

In this research study, the investigators are researching the activity and tolerability of apixaban in participants with HIT or HITT. The investigators believe that apixaban will work just as well as argatroban and will be more convenient for this population. The oral route of apixaban allows for the potential outpatient treatment of HIT or HITT which is both convenient and less expensive than treatment with argatroban.

Arms: arm 1: Patients with Heparin Induced Thrombocytopenia (HIT) will receive Apixaban, at an initial dose of 10 mg orally twice a day for 7 days followed by 5 mg twice a day for a total of 30 days. arm 2: Patients with Heparin Induced Thrombocytopenia with Thrombosis (HITT) will receive Apixaban, at an initial dose of 10 mg orally twice a day for 7 days followed by 5 mg twice a day for a total of 3 months.
Interventions: intervention 1: Apixaban
Intervention descriptions: intervention 1: Apixaban is an anticoagulant that works by inhibiting the coagulation factor, Factor Xa.

Protocol documents:
Prot_SAP_000.pdf: 
Page 1 
NCT #: NCT03594045 
DF/HCC Protocol #:  18-153 
TITLE:  A Phase II study to evaluate the efficacy and safety of apixaban in the treatment of 
heparin induced thrombocytopenia (HIT). 
Coordinating Center: 
MGH/CCPO (Cancer Center Protocol Office) 
Principal Investigator (PI): 
Rachel Rosovsky, MD 
Massachusetts General Hospital 
  
Other Investigators: 
Jean Marie Connors, MD 
Brigham and Women’s Hospital 
 
Jeffrey Zwicker, MD 
Beth Israel Deaconess Medical Center 
  
Statistician: 
Hui Zheng, PhD 
Massachusetts General Hospital 
  
NCI-Supplied Agent(s): none   
Other Agent(s): Apixaban, BMS 
IND #: 139741   
IND Sponsor: DF/HCC Investigator, Rachel Rosovsky, MD 
Protocol Type / Version # / Version Date: 
[v5/4.16.19] 


NCI Protocol #: 
DF/HCC Protocol #: 18-153 
Protocol Version Date: 10.26.2018 
 
2 
SCHEMA 
 
 
Phase II prospective open label study  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hospitalized patients on heparin therapy 
HIT positive 
HIT: Heparin Induced Thrombocytopenia 
SRA: Serotonin Release Assay 
LENI: Lower extremity non invasives 
DVT: deep vein thrombosis 
HITT: Heparin Induced Thrombocytopenia with Thrombosis 
 
 
 
+ Transition to apixaban 
If patient is started on an alternative anticoagulant prior to study, please refer to 
appendix E for instructions on how to transition to apixaban. 
 
Confirmed diagnosis of HIT or high clinical suspicion of HIT 
Treatment with Apixaban + 
HIT negative and suspicion no 
longer high 
HIT negative and high suspicion 
Obtain LENIs 
Continue Apixaban and send SRA 
d/c Apixaban 
and take off 
study 
Positive DVT or  
Evidence of a new clot after heparin 
exposure = HITT 
Negative DVT= isolated HIT 
Continue Apixaban for 30 days 
Continue Apixaban for 3 months 
Negative SRA, 
d/c Apixaban 
Continue Apixaban  
Positive SRA, 
continue Apixaban 


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TABLE OF CONTENTS 
 
SCHEMA .........................................................................................................................................2 
List of Abbreviations .......................................................................................................................6 
 
1. 
OBJECTIVES ......................................................................................................................7 
1.1 
Study Design ............................................................................................................7 
1.2 
Primary Objectives...................................................................................................7 
1.3 
Secondary Objectives...............................................................................................7 
2. 
BACKGROUND .................................................................................................................8 
2.1 
Study Disease(s).......................................................................................................8 
2.2 
IND Agent(s) ...........................................................................................................9 
2.3 
Rationale ..................................................................................................................9 
3. 
PARTICIPANT SELECTION ...........................................................................................11 
3.1 
Eligibility Criteria ..................................................................................................11 
3.2 
Exclusion Criteria ..................................................................................................12 
3.3 
Inclusion of Women and Minorities ......................................................................14 
4. 
REGISTRATION PROCEDURES ...................................................................................14 
4.1 
General Guidelines for DF/HCC and DF/PCC Institutions ...................................14 
4.2 
Registration Process for DF/HCC and DF/PCC Institutions .................................14 
 
5. 
TREATMENT AND/OR IMAGING PLAN .....................................................................15 
5.1 
Treatment Regimen ................................................................................................15 
5.2 
Pre-Treatment Criteria  ..........................................................................................16 
5.3 
Schedule and Description of Study Procedures .....................................................16 
5.4 
Agent Administration.............................................................................................20 
5.5 
Other Modalities or Procedures .............................................................................20 
5.6 
General Concomitant Medication and Supportive Care Guidelines ......................23 
5.7 
Criteria for Taking a Participant Off Protocol Therapy .........................................22 
5.8 
Duration of Follow Up ...........................................................................................23 
5.9 
Criteria for Taking a Participant Off Study ...........................................................23 
5.10 
Early Withdrawl .....................................................................................................25 
6. 
DOSING CHANGES.........................................................................................................24 
6.1 
Reversal of Anticoagulation Effect…………………………………………........26 
6.2 
Overdose…………………………………………………………………………27 
7. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS ............................25 
7.1 
Non-Serious Adverse Event ...................................................................................27 
7.2 
Laboratory Test Abnormalities ..............................................................................28 


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7.3 
Serious Adverse Event ...........................................................................................28 
7.4 
Overdose ................................................................................................................29 
7.5 
Other Safety Considerations ..................................................................................30 
7.6 
Adverse Events of Special Interest ........................................................................30 
7.7 
Expected Toxities...................................................................................................30 
7.8 
Adverse Event Characteristics ...............................................................................31 
7.9 
DF/HCC Expedited Adverse Event Reporting ......................................................32 
7.10 
Expedited Reporting to BMS .................................................................................32 
7.11 
Expedited Reporting to the Food and Drug Administration ..................................34 
7.12 
Expedited Reporting to Hospital Risk Management .............................................32 
7.13 
Routine Adverse Event Reporting .........................................................................35 
8. 
PHARMACEUTICAL AGENT INFORMATION ...........................................................35 
8.1 
Mechanism of Action .............................................................................................35 
8.2 
Pharmacodynamics ................................................................................................35 
8.3 
Special Populations ................................................................................................35 
8.4 
Pharmacokinetics ...................................................................................................36 
8.5 
Pharmaceutical .......................................................................................................38 
9. 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES ........................................41 
10. 
STUDY CALENDAR .......................................................................................................42 
11. 
MEASUREMENT OF EFFECT........................................................................................43 
11.1 
Other Response Parameters ...................................................................................43 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................44 
12.1 
Data Reporting .......................................................................................................44 
12.2 
Data Safety Monitoring..........................................................................................45 
12. 
STATISTICAL CONSIDERATIONS...............................................................................45 
12.1 
Study Design/Endpoints.........................................................................................45 
12.2 
Sample Size, Accrual Rate and Study Duration ....................................................47 
12.4 
Interim Monitoring Plan ........................................................................................47 
12.5 
Analysis of Primary Endpoints ..............................................................................47 
12.6 
Analysis of Secondary Endpoints ..........................................................................47 
12.7 
Reporting and Exclusions ......................................................................................47 
13. 
PUBLICATION PLAN .....................................................................................................48 
REFERENCES ..............................................................................................................................49 
APPENDIX A PERFORMANCE STATUS CRITERIA ..............................................................51 
APPENDIX B INFORMATION OF POSSIBLE DRUG INTERACTIONS ...............................54 
APPENDIX C APIXABAN PACKAGE INSERT ........................................................................56 


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APPENDIX D TRANSITION TO APIXABAN FROM OTHER AGENTS………...…………57 
 
APPENDIX E  CHILD-PUGH B and C DEFINITIONS………………………………............58 
 
 


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LIST OF ABBREVIATIONS 
 
AE 
 
Adverse Event 
ALT 
 
Alanine Aminotransferase 
ANC 
 
Absolute Neutrophil Count 
aPTT 
 
Activated Prothrombin Time 
AST 
 
Aspartate Aminotransferase 
BMS 
 
Bristol Meyer Squibb 
BUN 
 
Blood Urea Nitrogen 
CBC 
 
Complete Blood Count 
CO2 
 
Carbon Dioxide 
CRF 
 
Case Report Form 
DSMB 
 
Data Safety Monitoring Board 
DTI 
 
Direct Thrombin Inhibitor 
EIA  
 
Enzyme-linked Immunoassay 
FDA 
 
Food and Drug Administration 
HCG 
 
Human Chorionic Gonadotropin 
HIT 
 
Heparin-induced Thrombocytopenia 
HITT 
 
Heparin-induced Thrombocytopenia and Thrombosis 
IEC 
 
Independent Ethics Committee 
IND 
 
Investigational New Drug 
INR 
 
International Normalization Ratio 
IRB 
 
Institutional Review Board 
IV 
 
Intravenous 
K 
 
Potassium 
Kg 
 
Kilogram 
LMWH 
 
Low Molecular Weight Heparin 
Mg 
 
Magnesium 
mg 
 
Milligram 
MGH 
 
Massachusetts General Hospital 
Na 
 
Sodium 
Ng 
 
Nanogram 
NIH 
 
National Institutes of Health 
PF4 
 
Platelet Factor 4 
PO 
 
Per os or by mouth 
PT 
 
Prothrombin Time 
PTT 
 
Partial Thromboplastin Time 
RBC 
 
Red Blood Cells 
SAE 
 
Serious Adverse Event 
TEC 
 
Thromboembolic Complications 
UFH 
 
Unfractionated Heparin 
µg 
 
Microgram 
µL 
 
Microliter 
WBC 
 
White Blood Cells 


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1.                OBJECTIVES 
 
1.1 
Study Design 
 
This is a prospective, open label, single center study designed to evaluate the activity and 
tolerability of apixaban for the treatment of hospitalized patients with a confirmed diagnosis of 
isolated heparin induced thrombocytopenia or heparin induced thrombocytopenia with 
thrombosis (HIT and HITT, respectively).  
 
Hospitalized patients who have a confirmed diagnosis or highly suspicious symptoms of HIT 
will be treated with therapeutic dosing as approved by FDA of apixaban.  Study length will be 30 
days from the time of initiation of apixaban in patients with isolated HIT, defined as HIT without 
thrombosis, and 3 months for patients with HITT (heparin induced thrombocytopenia with 
thrombosis).  Treatment will continue until completion of the study, unacceptable toxicity or at 
the discretion of the investigator and patient.  Markers of disease activity (e.g. thrombocytopenia, 
TEC, death) will be assessed at baseline, daily during the initial treatment period with apixaban 
while patients are hospitalized and at 30-day follow-up for isolated HIT and 3 month follow up 
for HITT. 
 
1.2 
Primary Objectives 
 
To evaluate the activity of apixaban as monotherapy in patients with isolated heparin induced 
thrombocytopenia and HITT, as defined by the incidence of new symptomatic thromboembolic 
complications (TEC) within 30 days of the time of initiation of apixaban.  
 
1.3 
Secondary Objectives 
 
To evaluate the safety and efficacy of apixaban in the treatment of HIT and HITT within 30 days 
of enrollment, as defined by: 
 
o the composite incidence of all-cause death, amputation and new TEC  
o individual components of the composite endpoint 
o composite incidence of new TEC and major bleeding 
o the incidence of major bleeding 
o the time to platelet recovery * as a surrogate index of the activity of apixaban. 
 
*Time to platelet recovery is defined in section 11.1.4 
 
 
 


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2. 
BACKGROUND 
 
2.1 
Study Disease(s) 
 
Heparin-induced thrombocytopenia type-II (HIT) is a common and frequently severe syndrome 
characterized by thrombocytopenia and a prothrombotic state following exposure to 
unfractionated heparin (UFH) or low molecular weight heparin (LMWH).1 The incidence of HIT 
ranges from 0.3-5.0% depending on the patient population and the type and route of heparin 
used.1-4  It is an antibody-mediated reaction caused by the binding of platelet-activating IgG 
antibodies to platelet factor 4‒heparin complexes on the surface of platelets, and it typically 
manifests 4-10 days after the initiation of heparin therapy, but it can occur as quickly as a few 
hours in patients who have received heparin within the previous 100 days.5-7   
 
Patients diagnosed with HIT are at high risk for life-threatening thrombotic sequelae, up to 55%  
if untreated. 4  Recognition of the diagnosis, discontinuation of heparin therapy and immediate 
intervention with a non-heparin anticoagulant are critical for preventing thromboembolic 
complications (TEC) and restoring a normal platelet count. When HIT is accompanied by 
thrombosis, it is termed HITT; when it is not accompanied by thrombosis, it is termed isolated 
HIT.  Without evidence of TEC at the time of recognition, patients are regarded as having 
“isolated” HIT.  Such patients are recognized as having HIT due to a characteristic decline in the 
platelet count following the administration of heparin.  This decrease in the platelet count may 
occur immediately, as with a history of recent prior exposure (and thus antibodies are already 
present when heparin is recommenced), or after a delay of approximately five to ten days in 
patients without antibodies at baseline who are newly or repeatedly exposed to heparin.  The 
diagnosis may be confirmed objectively by one of a number of available laboratory tests 
including the serotonin-release assay, the platelet aggregation assay, or the heparin-platelet factor 
4 (PF4) enzyme-linked immunoassay (EIA). 5,8,9   While diagnostic specificity can be augmented 
by the use of functional studies, the heparin-PF4 EIA is the present, accepted standard for 
confirming the diagnosis of HIT in the United States.10 
 
Standard therapy in the United States for HIT(T) involves immediate administration of the direct 
thrombin inhibitor (DTI), argatroban. 10  Based on a significant reduction of a composite 
endpoint of thromboembolic events, limb amputation and death in patients with HIT(T) 
compared to a historical control, argatroban was approved by the FDA for use in patients with 
HIT or HIT with thrombosis (HITT).   A review of the two prospective clinical studies reporting 
argatroban administration in the acute treatment of isolated HIT reveals an incidence of TEC 
ranging from 6-8% among treated patients.11,12  However, two recently published studies report 
much higher TEC rates.  A case series aimed at identifying risk factors associated with the 
development of TEC report a rate of 25%.13   A “real world” analysis of 442 patients with a 
positive PF4 antibody test and heparin exposure had a composite endpoint of death, limb 
amputation or new thrombosis as the primary outcome.  This composite endpoint occurred in 
48% of the HITT patients and in 36% of the isolated HIT patients, of which 61% and 38% were 
treated with non-heparin anticoagulation, respectively.14  These recent studies more accurately 
reflect current trends. 
 
In the absence of thromboembolic disease, the duration of treatment is debated.  Based on a 


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retrospective cohort analysis documenting a high (52.8%) VTE risk at 30 days following 
diagnosis, a minimum of four weeks of therapeutic anticoagulation after normalization of the 
platelet count is appropriate.4  Early transition to warfarin is contraindicated due to the increased 
risk of microvascular thrombotic complications including skin necrosis and venous limb 
gangrene while patients are thrombocytopenic.15,16  Therefore practice standards require 
therapeutic anticoagulation with a DTI until the platelet count has demonstrated recovery, 
followed by a period of 5 or more days of continuous intravenous therapy with a DTI while 
transitioning to oral warfarin. 10,17   
 
2.2 
IND Agent: Apixaban 
 
Apixaban is an ideal alternative for the treatment of HIT or HITT because it is administered 
orally with fixed dosing, requires no routine coagulation monitoring and is FDA approved in the 
treatment of venous and arterial thromboembolism in other settings.18,19  It inhibits free and clot-
bound FXa resulting in decreased thrombin generation and thrombus formation and is 
structurally unrelated to heparin.   An in vitro study demonstrated that apixaban does not 
aggregate or activate platelets in the presence of HIT antibodies.20 Furthermore, a recent case 
series of 22 HIT patients showed that treatment with a short course of argatroban followed by a 
new oral anticoagulant (NOAC) was safe and effective in normalization of platelets and 
prevention of thrombosis.21 Moreover, there is one case report revealing that treatment with 
apixaban as monotherapy for the management of HIT was successful in terms of platelet 
recovery and lack of adverse events.22   Thus, apixaban is attractive alternative to DTIs for the 
treatment of HIT and HITT.   
  
2.3 
Rationale 
 
Heparin-induced thrombocytopenia type-II (HIT) is a common and often severe complication of 
heparin therapy.  Although the central feature of HIT is thrombocytopenia, the more worrisome 
complication is the development of arterial or venous thrombosis often referred to as heparin-
induced thrombocytopenia-thrombosis syndrome (HITT). The exact incidence of HIT associated 
thrombosis is not well established but studies demonstrate a range from 10% to as high as 55%.4   
In addition, the mortality associated with this complication has been reported to be as high as 
20%.4,9,10  Given this high rate of mortality and the awareness of prolonged thrombin generation 
even after heparin is discontinued, establishing the diagnosis, discontinuing heparin therapy and 
immediately intervening with a non-heparin anticoagulant are critical for preventing 
thromboembolic complications (TEC). 8 
 
Presently there is only one available alternative (Argatroban) to heparin that is FDA approved for 
HIT or HITT in this country that can be used as a bridge to coumadin.9,10  Argatroban is a direct 
thrombin inhibitor (DTI), administered intravenously, requires continuous laboratory monitoring, 
can cause excessive bleeding and is extremely costly.  Non FDA agents that are often used are 
fondaparinux or bivalirudin, the former requires an injection and the later is similar to 
Argatroban (and is approved for HIT in patients undergoing PCI).  Practice standards require 
therapeutic anticoagulation with a DTI until platelet count recovery, followed by 5 or more days 
of overlap while transitioning to oral warfarin with goal INR 2-3 for 1 month for patients with 
HIT and 3 months for patients with HITT.8,11 Thus, anticoagulating patients with HIT has 


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become a huge expense and burden on our health care system.   
 
There are several potential benefits to apixaban therapy compared to treatment with the direct 
thrombin inhibitor, argatroban.  Argatroban requires continuous intravenous administration, 
typically requiring protracted inpatient hospitalization for at least six to thirteen days based on 
the published mean duration of therapy with direct thrombin inhibitors reported in clinical trials. 
The oral route of apixaban allows for the potential outpatient treatment of HIT in selected 
patients, akin to the widespread use of subcutaneous danaparoid sodium in HIT prior to its 
withdrawal from the United States market.  Whereas direct thrombin inhibitors are unfamiliar to 
many practitioners and require careful titration of coagulation parameters, apixaban has a reliable 
pharmacokinetic profile and does not require plasma monitoring.  Furthermore, conversion to 
oral warfarin from a DTI, which is the current standard of care for HIT, is complicated by 
cessation of DTI anticoagulation while assessment of therapeutic warfarin dosing is determined.     
In addition to the requirement of inpatient hospitalization, direct thrombin inhibitors are costly 
medications compared to the cost of apixaban.  Thus, apixaban appears attractive as an 
alternative to direct thrombin inhibitor therapy in the treatment of HIT.   
 
Another desirable features of apixaban is the benefit of immediate anticoagulation in these 
highly prothrombotic and hypercoagulable patients. The incidence of TEC in HIT is greatest in 
the earliest phase of disease.4  Immediate alternative anticoagulation is, therefore, indicated in all 
patients where HIT is suspected.  However, therapeutic anticoagulation with a DTI may be 
difficult to achieve initially, in routine clinical practice.   In a prospective trial of argatroban in 
the treatment of HIT, only 83% of patients ultimately achieved therapeutic anticoagulation.11 
Pharmacokinetic studies of apixaban suggest that peak plasma concentration is reached within 3 
hours of administration, with a highly reproducible pharmacokinetic profile.23   Therefore, 
patients treated with apixaban are more likely to be effectively anticoagulated earlier in the 
course of the most hazardous phase of their disease. 
 
The ideal study would be a randomized controlled trial comparing apixaban with the FDA 
approved treatment for HIT, argatroban.  However, this is impractical due to cost and time 
constraints as it would require a large sample size and take years to accrue.  Although this is only 
a single site study, accruing to this study should not be difficult.  HIT is a frequent diagnosis at 
Massachusetts General Hospital (MGH).  There is an average of five positive HIT tests each 
week and over half of those are from patients who are in the hospital.  Over a 5 month period, 
from Oct 2015 to March 2016, there were 52 patients at MGH who received an intravenous 
direct thrombin inhibitor (DTI) - either argatroban or bivalirudin. This number is likely an 
underestimate of the number of HIT patients requiring treatment as it does not include those 
patients who were treated with fondaparinux alone.  Moreover, it is important to note that at 
MGH, patients diagnosed with HIT can only receive a DTI if approved by the hematology 
service.  Therefore, the principle investigator will be alerted to every HIT patient who potentially 
requires a DTI and if eligible, can offer the trial instead.   
 
 
 
3 
PARTICIPANT SELECTION 
 


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The potential participants in this study are hospitalized patients who receive heparin or low 
molecular weight therapy for various indications.  When a clinical diagnosis or high suspicion 
for HIT is apparent, heparin therapy should be discontinued. Before a patient starts apixaban, 
they will be screened to determine their eligibility to participate in the study based on the 
following inclusion/exclusion criteria: 
 
3.1 
Eligibility Criteria  
 
3.1.1 Hospitalized patients at MGH and participating Dana Farber/Harvard Cancer Center 
(DF/HCC) sites. 
 
3.1.2 Patient must have a 4 T score of ≥ 5 as calculated by the following criteria: 
 
o Thrombocytopenia 
 
Platelet count fall >50 percent and nadir ≥20,000/microL – 2 points 
 
Platelet count fall 30 to 50 percent or nadir 10 to 19,000/microL – 1 points 
 
Platelet count fall <30 percent or nadir <10,000/microL – 0 points 
o Timing of platelet count fall 
 
Clear onset between days 5 and 10 or platelet count fall at ≤1 day if prior heparin 
exposure within the last 30 days – 2 points 
 
Consistent with fall at 5 to 10 days but unclear (eg, missing platelet counts), onset 
after day 10, or fall ≤1 day with prior heparin exposure within 30 to 100 days – 1 
point 
 
Platelet count fall at <4 days without recent exposure – 0 points 
o Thrombosis or other sequelae 
 
Confirmed new thrombosis, skin necrosis, or acute systemic reaction after 
intravenous unfractionated heparin bolus – 2 points 
 
Progressive or recurrent thrombosis, non-necrotizing (erythematous) skin lesions, or 
suspected thrombosis that has not been proven – 1 point 
 
None – 0 points 
o Other causes for thrombocytopenia 
 
None apparent – 2 points 
 
Possible – 1 point 
 
Definite – 0 points 
 
3.1.3 
Patient must meet one of the following: 
o 
Have a confirmed diagnosis of HIT by Heparin-PF4 EIA or other accepted 
confirmatory test (serotonin-release assay, platelet aggregation assay).  
o 
Have a high clinical suspicion of HIT (either Heparin-PF4 result is pending, or 
Heparin-PF4 result is negative or not obtained but a confirmatory test is pending) 
 
Testing for HIT at MGH and participating DF/HCC sites is extremely reliable.  MGH 
and participating DF/HCC sites currently use an extensively validated PF4-H IgG-
based ELISA for HIT which has 94% specificity with a negative predictive value of 
99.7% and a sensitivity that is close to 95%. 
 


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3.1.4 
Patients can be treated with a non-heparin anticoagulant (such as argatroban, bivalirudin, 
or fondaparinux) for up to 7 days prior to enrollment.   
 
3.1.5  Age 18 years or older.    
 
3.1.6  ECOG performance status ≤2 
 
3.1.7 Participants must have organ and marrow function as defined below: 
 
− 
absolute neutrophil count 
 
≥1,500/mcL 
− 
AST(SGOT) and ALT(SGPT) ≤2.5 × institutional upper limit of normal 
− 
creatinine clearance 
 
≥25 mL/min as was used in the AMPLIFY trial16 
(Per Cockcroft-Gault formula) 
 
3.1.8  The effects of apixaban on the developing human fetus are unknown.  For this reason, 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for the 
duration of study participation.  Should a woman become pregnant or suspect she is 
pregnant while she or her partner is participating in this study, she should inform her 
treating physician immediately.  Men treated or enrolled on this protocol must also agree 
to use adequate contraception prior to the study, for the duration of study participation, 
and 4 months after completion of apixaban administration. 
 
3.1.9 Ability to understand and the willingness to sign a written informed consent document. 
 
3.2 
Exclusion Criteria 
 
3.2.1 
Patient requires anticoagulation for a mechanical heart valve. 
 
3.2.2 
Patient requires: 
o dual antiplatelet therapy,  
o treatment with aspirin at a dose of more than 162 mg daily 
 
3.2.3 
Patient has signs of active or ongoing clinically significant hemorrhage. 
 
3.2.4 
Patient has hereditary or acquired coagulopathy or bleeding disorder. 
 
3.2.5 
Patient has a contraindication to apixaban. 
 


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3.2.6 
Participants receiving any medications or substances that are inhibitors or inducers of  
cytochrome P-450 3A4 or p-glycoprotein are ineligible.  Because the lists of these 
agents are constantly changing, it is important to regularly consult a frequently-
updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical 
reference texts such as the Physicians’ Desk Reference may also provide this 
information.  As part of the enrollment/informed consent procedures, the patient will 
be counseled on the risk of interactions with other agents, and what to do if new 
medications need to be prescribed or if the patient is considering a new over-the-
counter medicine or herbal product.   
 
3.2.7 
Patient has severe renal insufficiency (CrCl <25 ml/min–as used in the AMPLIFY 
trial) 16  
 
3.2.8 
Patient has hepatic disease (including Child-Pugh B and C) associated with 
coagulopathy or clinically relevant bleeding risk.   See appendix F for definition 
 
3.2.9 
Recent (previous seven days), or complicated lumbar puncture or epidural catheter 
placement or removal.  
 
3.2.10 
Patient has high potential need to undergo a surgical or major invasive procedure in 
the near future. 
 
3.2.11 
Patient has a history of uncorrected cerebral aneurysm, intracranial tumor or 
hemorrhagic cerebrovascular accident. 
 
3.2.12 
Patient refuses to receive transfused blood products should this intervention become 
clinically indicated. 
 
3.2.13 
Patient is taking or has been taking an investigational drug within the previous 30 
days prior to enrollment. 
 
3.2.14 
In the judgment of the investigator, any disease or circumstance that would interfere 
with the objectives of the study, that places the patient at undue, increased risk by 
enrolling in the study, or which limits the ability either to provide signed informed 
consent or comply with the trial protocol. 
 
3.2.15 
Participants with known brain metastases should be excluded from this clinical trial 
because of their poor prognosis and because they often develop progressive 
neurologic dysfunction that would confound the evaluation of neurologic and other 
adverse events. 
 
3.2.16 
History of allergic reactions attributed to compounds of similar chemical or biologic 
composition to apixaban. 
 


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3.2.17 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with 
study requirements. 
 
3.2.18 
Pregnant women are excluded from this study because apixaban is a Class B agent 
with unknown potential for teratogenic or abortifacient effects.   It is unknown 
whether apixaban or its metabolites are excreted in human milk. Because there is an 
unknown but potential risk for adverse events in nursing infants secondary to 
treatment of the mother with apixaban, breastfeeding should be discontinued if the 
mother is treated with apixaban.  
 
3.2.19 
Prior treatment with a non-heparin anticoagulant while awaiting study enrollment is 
not an exclusion. 
 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
 
4 
REGISTRATION PROCEDURES 
 
4.1 
General Guidelines for DF/HCC Institutions 
 
Institutions will register eligible participants in the Clinical Trials Management System (CTMS) 
OnCore. Registrations must occur prior to the initiation of any protocol-specific therapy or 
intervention. Any participant not registered to the protocol before protocol-specific therapy or 
intervention begins will be considered ineligible and registration will be denied. 
 
An investigator will confirm eligibility criteria and a member of the study team will complete the 
protocol-specific eligibility checklist. 
 
Following registration, participants may begin protocol-specific therapy and/or intervention. 
Issues that would cause treatment delays should be discussed with the Overall Principal 
Investigator (PI). If the subject does not receive protocol therapy following registration, the 
subject must be taken off-study in the CTMS (OnCore) with an appropriate date and reason 
entered.  
 
 
4.2 
Registration Process for DF/HCC Institutions 
 
DF/HCC Standard Operating Procedure for Human Subject Research Titled Subject Protocol 
Registration (SOP #: REGIST-101) must be followed.   
 
 


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Protocol Version Date: 10.26.2018 
 
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5 
TREATMENT AND/OR IMAGING PLAN 
 
5.1 
Treatment Regimen 
 
Patients eligible for the study will receive the standard of care and FDA approved dosing of 
apixaban.  Platelet count recovery in patients with HIT is typically 5-7 days.  Warkentin 
demonstrated that patients with isolated HIT (HIT without thrombosis) have an increased risk of 
thrombosis for up to 30 days after diagnosis.4   Therefore, for patients with isolated HIT (HIT 
without thrombosis), patients will receive apixaban, 10 mg twice a day for 7 days followed by 5 
mg twice a day for 23 days, for a total of 30 days of apixaban dosing.  For patients with HITT, 
patients will receive apixaban, 10 mg twice a day for 7 days followed by 5 mg twice a day for 83 
days, for a total of 90 days of apixaban dosing, which are the current CHEST guidelines for 
duration of treatment for patients with provoked VTE.24  The proposed apixaban dosing regimen 
is taken from the current FDA approved dosing schedule for the treatment of venous 
thromboembolism [VTE] with apixaban which is 10 mg twice daily for 7 days followed by 5 mg 
twice daily thereafter.    
 
Treatment will initially be administered on an inpatient basis but once patient is medically 
cleared to be discharged, the remaining treatment will be administered on an outpatient basis.  
Reported adverse events and potential risks are described in Section 7.  Appropriate dose 
modifications are described in Section 6.  No investigational or commercial agents or therapies 
other than those described below may be administered with the intent to treat the participant. 
Regimen Description 
Agent 
Premedications; 
Precautions 
Dose 
Route 
Schedule* 
Length of 
treatment 
Apixaban 
No 
premedications 
required 
 
10 mg 
twice a day 
Oral 
For the first 7 
days** 
1 month (30 
days) total for 
HIT patients and 
3 months (90 
days) total for 
HITT patients  
 
Apixaban 
No 
premedications 
required 
5 mg twice 
a day 
Oral 
To start this dose 
after patient 
completes the 
first 7 days with 
the 10 mg twice a 
day dose.** 
*     This is the FDA approved dose for apixaban for prevention and treatment of venous 
thromboembolism.  
**  Patients will not start the 5 mg dose prior to 7 days as this is the FDA approved dosing 
structure.   
 
NOTE:  Patients will be requested to maintain a medication diary of each dose of medication.  
The medication diary will be returned to clinic staff at the end of the study (one month for HIT 
patients and 3 months for HITT patients). 
 


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Protocol Version Date: 10.26.2018 
 
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5.2 
Pre-Treatment Criteria 
 
Prior to initiation of treatment on D1, participants’ labs must re-meet eligibility. Participants 
must have organ and marrow function as defined by absolute neutrophil count ≥1,500/mcL, 
AST(SGOT) and ALT(SGPT) ≤2.5 × institutional upper limit of normal and creatinine clearance 
≥25 mL/min (as was used in the AMPLIFY trial).  
 
5.3 
Schedule and Description of Study Procedures (requirements also detailed in study calendar) 
 
5.3.1 
Screening and Pre-Enrollment Procedures (Day -7 to Day 1) 
 
Patients with suspected heparin-induced thrombocytopenia will be screened to determine 
if they meet study eligibility criteria.  Prior to initiation of any study procedures, a written 
IRB–approved informed consent will be obtained.  Much of the information listed below 
will be obtained at the time of determining eligibility. Eligibility is verified after consent, 
and patients are enrolled only after eligibility is determined.    
 
The window for baseline screening/assessment is up to 7 days prior to start of treatment. 
 
Upon consent, the following study procedures will be performed: 
 
5.3..1 
Confirmatory Laboratory Test for the Diagnosis of HIT  
• 
Heparin-PF4 EIA or accepted other confirmatory test (e.g. serotonin-release 
assay, platelet aggregation assay) is required if not already recorded in the 7 days 
prior to study treatment initiation. 
• 
If the patient’s initial HIT confirmatory test is negative, but the patient 
presentation is highly suspect for HIT, perform a serotonin release assay. 
• 
Result may be pending at the time of enrollment. 
 
5.3..2 
Demographic and Medical History  
• 
Date of birth, gender, race, hospital service. 
• 
Past medical history of significant medical/surgical disease and previous 
hospitalization. 
• 
History of thrombotic event(s). 
• 
History of HIT and/or previous exposure to heparin/LMWH.  
• 
Reason for initial hospitalization.  
• 
Reason for initiation of heparin/LMWH. 
• 
Type of heparin treatment, route of administration and length of therapy. 
• 
Previous use of other anticoagulation therapy  
• 
Concomitant medications. 
 
5.3..3 
Physical Examination, including: 
• 
Height, weight. (Height documented within the month prior to D1 is acceptable) 
• 
ECOG 


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Protocol Version Date: 10.26.2018 
 
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• 
Vital signs (temperature, pulse, respirations, blood pressure, oxygen saturation).  
• 
Clinical assessment for signs and symptoms of thromboembolic complications 
and any significant findings. 
 
5.3..4 
Laboratory Tests 
• 
Record pre-heparin CBC with platelet count and blood coagulation profile.  
• 
Urine or serum HGC pregnancy test in women of childbearing age (acceptable if 
performed within 7 days prior to initiation of study drug regimen). 
• 
CBC: hemoglobin, hematocrit, WBC with differential, and platelet count. 
• 
Blood coagulation profile: Activated partial thromboplastin time (aPTT), 
prothrombin time/international normalized ratio (PT/INR).  
• 
Serum Chemistries: creatinine, BUN, Na, K, CO2 and glucose.  
• 
Hepatic Profile: total bilirubin, AST, ALT. 
 
5.3.2 
Imaging (Day -7 to Day +3) 
• 
As part of standard of care, all patients with confirmed HIT or high suspicion of 
HIT undergo bilateral lower extremity non invasive testing to rule out deep vein 
thrombosis. LENI is not required if the patient is diagnosed with a Pulmonary 
Embolism.   
• 
This can occur anytime from Day -7 to Day +3.  Only one test is required. 
 
5.3.3 
Initiation of Therapy:  Day 1  
 
Once the patient has been consented and is determined to meet inclusion/exclusion 
criteria as described above in Section 3.1 and 3.2, the following study procedures will be 
performed. These assessments do not need to be repeated if Screening was conducted on 
D1. 
 
• 
Physical Exam 
• 
Clinical Assessment for signs and symptoms of TEC and any significant findings 
• 
Vital signs  
• 
Weight 
• 
ECOG 
• 
Laboratory tests:  
o CBC: hemoglobin, hematocrit, WBC with differential, and platelet count  
o Chemistries: creatinine, BUN, Na, K, CO2 and glucose 
o Hepatic panel: total bilirubin, AST, ALT 
o Coagulation profile: aPTT, PT/INR 
• 
Record Concomitant Medications 
• 
Assess and Record Adverse Events 
• 
Initiation of Therapy: dispense study medication and diary 
o Administer study medication: Apixaban 
o Initiate daily oral therapy at 10 mg twice daily for 7 days followed by 5 
mg twice daily thereafter.   
 


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Protocol Version Date: 10.26.2018 
 
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5.3.4 
Hospital Course: Day 2 - Day of Discharge:   
 
The following procedures will be done on a daily basis until discharge from the hospital: 
 
• Clinical Assessment for signs and symptoms of thromboembolic complications 
and any significant findings. 
• Vital signs 
• Laboratory Tests: 
o CBC: hemoglobin, hematocrit, WBC with differential, and platelet count 
o Chemistry Panel: creatinine, BUN, Na, K, CO2 and glucose 
• Assess and record Adverse Events 
• Record Concomitant Medications 
• Record all doses of administered Apixaban (from the day it was initiated). 
 
Before discharge, ensure enough study medication is dispensed to last at least until the 
30 Day Follow Up visit (for HIT) or the 90 Day Follow Up visit (for HITT). 
 
5.3.5 Follow-up: Day 30 (+/- 5 days)  
 
The patient will be assessed on Day 30 (+ 5 days) from initiation of therapy, preferably in 
clinic.  If clinic follow up is feasible, all of the following data must be recorded.  If 
patient is unable to come to clinic (ie due to living in another city or unable to travel), day 
30 follow up can be completed by telephone interview and the labs, exam and vitals will 
not be recorded.   
 
The following data must be recorded: 
 
• Summary of patient’s clinical course 
• Any adverse events that occurred between Day of Discharge through Day 30 
including signs and symptoms of TEC. 
• CBC, chemistries, coagulation profile* 
• Physical exam and vital signs* 
• Concomitant Medications 
• For patients discharged on apixaban: 
o Retrieve study medication and diary  
o Record the stop date of discontinuation of apixaban. 
 
*unable to obtain if follow up is telephone interview 
 
5.3.6 
Follow-up for patients with HITT: Day 90 (+/- 5 days) 
 


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Protocol Version Date: 10.26.2018 
 
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The patient will be assessed on Day 90 (+ 5 days), from initiation of therapy, preferably 
in clinic.  If clinic follow up is feasible, all of the following data must be recorded.  If 
patient is unable to come to clinic (ie due to living in another city or unable to travel), day 
90 follow up can be completed by telephone interview and the labs, exam and vitals will 
not be recorded.   
 
The following data must be recorded: 
 
• Summary of patient’s clinical course 
• Any adverse events that occurred between Day of Discharge through Day 90 
including signs and symptoms of TEC. 
• CBC, chemistries, coagulation profile* 
• Physical exam and vital signs* 
• Concomitant Medications 
• For patients discharged on apixaban: 
o Retrieve study medication and diary 
o Record the stop date of discontinuation of apixaban. 
 
*unable to obtain if follow up is telephone interview 
 
5.3.7 
Follow-up 30 days after last dose of therapy (+/- 5 days) 
 
The patient will be assessed on 30 days (+ 5 days), after last dose of therapy.  If clinic 
follow up is feasible, all of the following data must be recorded.  If patient is unable to 
come to clinic (ie due to living in another city or unable to travel), this follow up can be 
completed by telephone interview and the labs, exam and vitals will not be recorded.   
 
The following data must be recorded: 
 
• Summary of patient’s clinical course 
• Any adverse events through 30 days after the last dose of therapy including signs and 
symptoms of TEC. 
• CBC, chemistries* 
• Physical exam and vital signs* 
• Concomitant Medications 
 
*unable to obtain if follow up is telephone interview 
 


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Protocol Version Date: 10.26.2018 
 
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5.3.8 Unscheduled Additional Visits 
 
 
For any unscheduled visits, between Day of Discharge and Day 30 for isolated HIT and 
Day 90 for HITT, that are related to HIT and require hospitalization and treatment, the 
following procedures should be performed if possible (ie will not be possible if patient is 
admitted to an outside hospital or over the weekend/evening and discharged before study 
team available) 
 
• Clinical Assessment  for signs and symptoms of thromboembolic complications and 
any significant findings. 
• Physical exam  
• Vitals 
• Summary of patient’s clinical course, including any imaging if performed 
• Laboratory Tests: 
o CBC: hemoglobin, hematocrit, WBC with differential, and platelet count 
o Chemistries: creatinine, BUN, Na, K, CO2 and glucose  
o Hepatic panel: total bilirubin, AST, ALT 
o Blood coagulation profile: aPTT, PT/INR  
• Assess and record Adverse Events 
• Record Concomitant Medications 
• Record all doses of apixaban.  
 
5.3.9 Evaluation of Symptomatic Thromboembolic Complications (TEC).  
 
Patients will be evaluated for thrombotic events at each visit.  The diagnosis of 
symptomatic, venous or arterial thrombosis will be determined by the primary 
investigator and/or treating physician based on established clinical signs and symptoms 
and where indicated (as for VTE) by a confirmatory, objective diagnostic test per the 
accepted standard of care. 
 
5.3.10 Treatment of Symptomatic Thromboembolic Complications (TEC).  
 
Treatment of symptomatic TEC will be instituted by the primary investigator and/or 
treating physician per their standard of care. Patients who develop symptomatic TEC, 
which is the primary endpoint for this study, will be followed for safety throughout the 
study follow-up period.  
 
 
5.4 
Agent Administration.  
 
Apixaban will be supplied by BMS.   
 


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Protocol Version Date: 10.26.2018 
 
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5.4.1 Administration and Dosing.   
 
Apixaban will be initiated at 10 mg twice a day orally for the first 7 days.  After 7 days, 
the dose of apixaban will be changed to 5 mg twice daily.    This dosing regimen is the 
FDA approved dose per package insert.   Per FDA approved guidelines, there is no 
requirements for dose modifications once patients meets inclusion and exclusion criteria. 
 
For patients who are unable to swallow whole tablets, 5 mg APIXABAN tablets 
may be crushed and suspended in water, 5% dextrose in water (D5W), or apple juice, 
or mixed with applesauce and promptly administered orally. Alternatively, APIXABAN 
tablets may be crushed and suspended in 60 mL of water or D5W and promptly delivered 
through a nasogastric tube. Crushed APIXABAN tablets are stable in water, D5W, apple 
juice, and applesauce for up to 4 hours. 
 
No hydration or pre-medications are required prior to administration of apixaban. There 
are no dietary restrictions when taking apixaban. There are no specific precautions 
necessary when administering apixaban. 
 
5.4.2 Dosage Forms and Strengths 
 
• 5 mg, pink, oval-shaped, biconvex, film-coated tablets with “894” debossed on one 
side and “5” on the other side.  
 
• Drug may be dispensed per institutional standard, including repackaging.  
 
5.4.3 Drug Diary 
 
Patients will be requested to maintain a medication diary of each dose of medication.  
The medication diary will be returned to clinic staff at the end of the study (one month 
for HIT patients and 3 months for HITT patients).   
 
5.4.4 Missed Dose or Vomited Dose 
 
If a dose of APIXABAN is not taken at the scheduled time, the dose should be taken as 
soon as possible on the same day and twice-daily administration should be resumed. The 
dose should not be doubled to make up for a missed dose.  
 
For vomited dose(s): If a single episode of vomiting, the dose should be taken at the next 
scheduled dose timings. If repeated vomiting and the patient is unable to retain any oral 
medications, the patient should contact his/her doctor immediately and he/she may need 
to be either temporarily discontinued from the study medication or permanently 
discontinued from the study drug.  An alternative medication will be necessary if 
apixaban is stopped. 
 
5.5 
Other Modalities or Procedures 
 


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Protocol Version Date: 10.26.2018 
 
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Once patients are diagnosed with HIT as part of standard of care or there is high suspicion of 
HIT, patients will undergo bilateral lower extremity non invasive ultrasound (LENI) to 
determine the presences of deep vein thromboses. If DVTs are identified, there will be no change 
in therapy.  Presence of DVT will affect the length of anticoagulation.  If patients have DVT, this 
would qualify as HITT and the patient will require 3 months of apixaban instead of 30 days as 
indicated for isolated HIT.  If LENI is negative for DVT, but patient develops and is diagnosed 
with a clot elsewhere after heparin exposure, this would also qualify as HITT and will require 3 
months of apixaban. The LENI is not required if the patient is diagnosed with a Pulmonary 
Embolism. 
 
5.6 
General Concomitant Medication and Supportive Care Guidelines 
 
Because there is a potential for interaction of apixaban with other concomitantly administered 
drugs through the cytochrome P450 system or the p-glycoprotein system, the case report form 
must capture the concurrent use of all other drugs, over-the-counter medications, or alternative 
therapies.  Appendix C presents guidelines for identifying medications/substances that could 
potentially interact with the study agent(s). 
 
The following medications are not permitted in the protocol:  
 
• 
Any other drug or biological agent with anticoagulation action. 
• 
Any other drug that is known to interact negatively with the study drug. 
• 
Investigational agents. 
• 
Myelosuppressive chemotherapy. 
• 
Treatment with aspirin at a dose of more than 162 mg daily. 
 
5.7 
Criteria for Taking a Participant Off Protocol Therapy 
 
Duration of therapy will be one month for patients with isolated HIT and 3 months for patients 
with HITT.  In the absence of treatment delays due to adverse event(s), treatment may continue 
for 1 month for isolated HIT and 3 months for HITT or until one of the following criteria applies: 
 
• 
Patient had initial high clinical suspicion for HIT as defined in section 3.1.2 but 
testing with PF4 or other accepted confirmatory test (serotonin-release assay, platelet 
aggregation assay) returned negative. 
 
• 
New symptomatic TEC 
 
• 
Intercurrent illness that prevents further administration of treatment 
 
• 
Major bleed (See Section 6) 
 
• 
Patient becomes pregnant 
 
• 
Unacceptable adverse event(s) 
 


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Protocol Version Date: 10.26.2018 
 
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• 
Participant demonstrates an inability or unwillingness to comply with the oral 
medication regimen and/or documentation requirements 
 
• 
Patient refuses to receive transfused blood products should this intervention become 
clinically indicated 
 
• 
Participant decides to withdraw from the protocol therapy 
 
• 
General or specific changes in the participant's condition render the participant 
unacceptable for further treatment in the judgment of the treating investigator.  It is 
requested that premature discontinuation of a patient should be discussed immediately 
with the principal investigator, Dr. Rachel Rosovsky, 617-726-2000. 
 
Participants will be removed from the protocol therapy when any of these criteria apply.  The 
reason for removal from protocol therapy, and the date the participant was removed, must be 
documented in the case report form (CRF). Alternative care options will be discussed with the 
participant. 
 
When a participant is removed from protocol therapy and/or is off of the study, the relevant Off-
Treatment/Off-Study information will be updated in OnCore. 
 
5.8 
Duration of Follow Up 
 
Participants will be followed for 30 days after last dose of study drug. Patients who are not 
hospitalized at the time of follow up will be seen in the outpatient clinic.   Participants removed 
from protocol therapy for unacceptable adverse event(s) will be followed until resolution or 
stabilization of the adverse event. 
 
5.9 
Criteria for Taking a Participant Off Study 
 
Participants will be removed from study when any of the following criteria apply: 
 
• Lost to follow-up 
• Withdrawal of consent for data submission 
• Death 
 
The reason for taking a participant off study, and the date the participant was removed, must be 
documented in the case report form (CRF). In addition, the study team will ensure Off 
Treatment/Off Study information is updated in OnCore in accordance with DF/HCC policy 
REGIST-101. 
 
5.10 
Early Withdraw 
 
Any patient who is enrolled in the study, but withdraws prematurely at any time for any reason 
before the end of their Day 30 follow-up visit (or phone call) for isolated HIT or Day 90 follow 
up visit (or phone call) for HITT, is considered an early withdraw and will not be replaced.  A 


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Protocol Version Date: 10.26.2018 
 
24 
complete set of data including the reason for the early withdraw will be collected on each patient 
through the time of withdraw.  Every effort will be made to ascertain patient safety and survival 
information at the Day 30 follow-up time-point for isolated HIT and Day 90 for HITT. 
 
Note:  Date of follow up refers to the total days since initiation of treatment. 
 
6 
DOSING CHANGES  
 
Dose changes will be made as indicated in the following table(s). The descriptions and grading 
scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.0 will be utilized for dose changes. A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP website 
 http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm.  
 
 
Bleeding 
Management of Patient 
Management Of Apixaban 
≤ Grade 1 
Mild, intervention not indicated 
 
Continue apixaban and monitor 
closely 
Grade 2 
Symptomatic and medical 
intervention indicated  
Stop apixaban, take off protocol 
Grade 3 
Transfusion, interventional 
radiology, endoscopic, or operative 
intervention indicated; radiation 
therapy (i.e., hemostasis of 
bleeding site) 
 
Stop apixaban, take off protocol 
Grade 4 
Life-threatening consequences; 
major urgent intervention indicated 
Stop apixaban, take off protocol 
Grade 5 
Death 
Stop apixaban, take off protocol 
 
Apixaban will also be stopped and patient will be taken off protocol for any major bleed.   
Decisions regarding further treatment for patients who experience a major hemorrhagic event 
will be deferred to the primary team.  They will be followed to the end of the study in an 
intention-to-treat analysis. 
 
Major bleeding is defined as overt bleeding and: 
• associated with a decrease in hemoglobin of ≥ 2 g/dL, or 
• leading to a transfusion of ≥ 2 units of packed red blood cells or whole blood, or 
• occurring in a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, 
intramuscular with compartment syndrome, retroperitoneal, or 
• contributing to death. 
 
6.1 Reversal of Anticoagulation Effect 
 
A specific antidote for Apixaban is not available, and there is no established way to reverse 
bleeding in patients taking Apixaban. The pharmacodynamic effect of APIXABAN can be 


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Protocol Version Date: 10.26.2018 
 
25 
expected to persist for at least 24 hours after the last dose, i.e., for about two drug half-lives. Use 
of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated 
prothrombin complex concentrate or recombinant factor VIIa, has not been evaluated in clinical 
studies. Activated oral charcoal reduces absorption of apixaban, thereby lowering apixaban 
plasma concentration [see Overdosage below]. Hemodialysis does not appear to have a 
substantial impact on apixaban exposure. Protamine sulfate and vitamin K are not expected to 
affect the anticoagulant activity of apixaban. There is no experience with antifibrinolytic agents 
(tranexamic acid, aminocaproic acid) in individuals receiving apixaban. There is no experience 
with systemic hemostatic agents (desmopressin and aprotinin) in individuals receiving apixaban 
and they are not expected to be effective as a reversal agent. 
 
Because there is no specific antidote to reverse the effect of apixaban, the following steps are 
recommended for subjects with ongoing life-threatening bleeding (bleeding resulting in 
hemodynamic compromise requiring intervention or any intracranial hemorrhage): 
 
• Withhold study drug and all antiplatelets/anticoagulants; 
• Institute standard of care for life-threatening bleeding (large bore IV or central venous 
line, type and crossmatch blood, admit to the intensive care unit, provide hemodynamic 
and respiratory support); 
• Administer packed red blood cells (or whole blood) as needed. 
 
If life-threatening bleeding persists, it is recommended to contact the PI to discuss subject 
management.  
 
6.2 Overdose 
 
There is no antidote to Apixaban. Overdose of Apixaban increases the risk of bleeding. In 
controlled clinical trials, orally administered apixaban in healthy subjects at doses up to 50 mg 
daily for 3 to 7 days (25 mg twice daily for 7 days or 50 mg once daily for 3 days) had no 
clinically relevant adverse effects. 
 
In healthy subjects, administration of activated charcoal 2 and 6 hours after ingestion of 
a 20-mg dose of apixaban reduced mean apixaban AUC by 50% and 27%, respectively. 
Thus, administration of activated charcoal may be useful in the management of apixaban 
overdose or accidental ingestion. 
 
 
7 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug and 
that does not necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of investigational product, whether or not considered 
related to the investigational product. 
 


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Protocol Version Date: 10.26.2018 
 
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The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE).  
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.) 
 
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, meets the 
definition of an SAE or AESI, or is considered by the investigator to be a clinically significant 
change from baseline. 
 
7.1 Nonserious Adverse Event 
 
A nonserious adverse event is an AE not classified as serious.  
• Nonserious Adverse Events are to be provided to BMS in aggregate via interim or final 
study reports as specified in the agreement or, if a regulatory requirement [e.g. IND US 
trial] as part of an annual reporting requirement.  
 
7.1.1 Nonserious Adverse Event Collection and Reporting 
 
The collection of nonserious AE information should begin following the subject’s written consent 
to participate in the study. All nonserious adverse events (not only those deemed to be treatment-
related) should be collected continuously during the treatment period and for a minimum of 30 
days following the last dose of study treatment.  
 
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 study drug and for those present at the end of study treatment as appropriate.  
Nonserious Adverse Events are provided to BMS via annual safety reports (if applicable), and 
interim or final study reports. 
 
7.2 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 participant to have study drug discontinued or 
interrupted 
• any laboratory abnormality that required the subject to receive specific corrective therapy.  
 
It is expected that wherever possible, the clinical rather than laboratory term would be used by the 
reporting investigator (eg, anemia versus low hemoglobin value). 
 


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7.3 Serious Adverse Event 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
• results in death 
• is life-threatening (defined as an event in which the participant 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 [eg, 
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 (eg, pathogenic or nonpathogenic) via the 
study drug is an SAE.  
Although pregnancy, overdose, potential drug-induced liver injury (DILI) and cancer are not 
always serious by regulatory definition, these events must be handled as SAEs. 
Any component of a study endpoint that is considered related to study therapy should be reported 
as an SAE if it meets the above SAE definition (eg, death is an endpoint, if death occurred due to 
anaphylaxis, anaphylaxis must be reported). 
NOTE: The following hospitalizations are not considered SAEs:  
− a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening event) 
− elective surgery, planned prior to signing consent 
− admissions as per protocol for a planned medical/surgical procedure 
− routine health assessment requiring admission for baseline/trending of health status (eg, 
routine colonoscopy) 
− Medical/surgical admission other than to remedy ill health and planned prior to entry 
into the study. 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 (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
 


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Protocol Version Date: 10.26.2018 
 
28 
7.4 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 SAEs. 
 
7.5 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 as a nonserious or serious adverse 
event, as appropriate, and reported accordingly. 
 
7.6 Adverse Events of Special Interest 
 
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. 
 
7.7 
Expected Toxicities 
 
7.7.1 
Adverse Events List for Apixaban 
 
The safety of APIXABAN has been evaluated in non HIT or non HITT venous 
thromboembolism patient populations in the AMPLIFY and AMPLIFY-EXT studies, including 
2676 patients exposed to APIXABAN 10 mg twice daily, 3359 patients exposed to APIXABAN 
5 mg twice daily, and 840 patients exposed to APIXABAN 2.5 mg twice daily. 
 
Common adverse reactions (≥1%) were gingival bleeding, epistaxis, contusion, hematuria, rectal 
hemorrhage, hematoma, menorrhagia, and hemoptysis.  
 
AMPLIFY Study 
The mean duration of exposure to APIXABAN was 154 days and to enoxaparin/warfarin was 
152 days in the AMPLIFY study. Adverse reactions related to bleeding occurred in 417 (15.6%) 
APIXABAN-treated patients compared to 661 (24.6%) enoxaparin/warfarin treated patients. The 
discontinuation rate due to bleeding events was 0.7% in the APIXABAN-treated patients 
compared to 1.7% in enoxaparin/warfarin-treated patients in the AMPLIFY study. 
 
In the AMPLIFY study, APIXABAN was statistically superior to enoxaparin/warfarin in the 
primary safety endpoint of major bleeding (relative risk 0.31, 95% CI [0.17, 0.55], P-value 
<0.0001). 
 
Adverse reactions occurring in 1-3% of patients in the AMPLIFY study include: epistaxis, 
contusion, hematuria, menorrhagia, hematoma, hemoptysis, rectal hemorrhage, gingival 
bleeding. 


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29 
 
AMPLIFY-EXT Study 
The mean duration of exposure to APIXABAN was approximately 330 days and to placebo was 
312 days in the AMPLIFY-EXT study. Adverse reactions related to bleeding occurred in 219 
(13.3%) APIXABAN-treated patients compared to 72 (8.7%) placebo-treated patients. The 
discontinuation rate due to bleeding events was approximately 1% in the APIXABAN-treated 
patients compared to 0.4% in those patients in the placebo group in the AMPLIFY-EXT study. 
 
Adverse reactions occurring in 1-2% of patients in the AMPLIFY-EXT study include: epistaxis, 
contusion, hematuria, hematoma, gingival bleeding. 
 
Other Adverse Reactions 
Less common adverse reactions in APIXABAN-treated patients in the AMPLIFY or 
AMPLIFYEXT studies occurring at a frequency of ≥0.1% to <1%: 
 
Blood and lymphatic system disorders: hemorrhagic anemia 
 
Gastrointestinal disorders: hematochezia, hemorrhoidal hemorrhage, gastrointestinal 
hemorrhage, hematemesis, melena, anal hemorrhage 
 
Injury, poisoning, and procedural complications: wound hemorrhage, postprocedural 
hemorrhage, traumatic hematoma, periorbital hematoma 
 
Musculoskeletal and connective tissue disorders: muscle hemorrhage 
 
Reproductive system and breast disorders: vaginal hemorrhage, metrorrhagia, 
menometrorrhagia, genital hemorrhage 
 
Vascular disorders: hemorrhage 
 
Skin and subcutaneous tissue disorders: ecchymosis, skin hemorrhage, petechiae 
 
Eye disorders: conjunctival hemorrhage, retinal hemorrhage, eye hemorrhage 
 
Investigations: blood urine present, occult blood positive, occult blood, red blood cells 
urine positive 
 
General disorders and administration-site conditions: injection-site hematoma, vessel 
puncture-site hematoma 
 
Please refer to the approved apixaban U.S prescribing information for a complete listing of 
adverse events  
 
7.8 
Adverse Event Characteristics 
 
• CTCAE term (AE description) and grade:  The descriptions and grading scales found 


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Protocol Version Date: 10.26.2018 
 
30 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be 
downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic applications/ctc.htm. 
 
• For expedited reporting purposes only:   
- 
AEs for the agent(s) that are listed above should be reported only if the adverse event 
varies in nature, intensity or frequency from the expected toxicity information which 
is provided. 
- 
Other AEs for the protocol that do not require expedited reporting are outlined in the 
next section (Expedited Adverse Event Reporting) under the sub-heading of Protocol-
Specific Expedited Adverse Event Reporting Exclusions. 
 
• Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
7.9 
Expedited Adverse Event Reporting  
 
7.9.1 In the event of an unanticipated problem or life-threatening complications 
treating investigators must immediately notify the Overall PI. 
 
7.9.2 Investigators must report to the Overall PI any serious adverse event (SAE) that 
occurs after the initial dose of study treatment, during treatment, and within 30 
days after the last dose of treatment. 
 
7.9.3 DF/HCC Expedited Reporting Guidelines 
 
Investigative sites within DF/HCC will report AEs directly to the DFCI Office for 
Human Research Studies (OHRS) per the DFCI IRB reporting policy.  
 
7.9.4 Protocol-Specific Expedited Adverse Event Reporting Exclusions:  
 
None 
 
7.10 
Expedited Reporting to BMS 
 
Following the subject’s written consent to participate in the study, all SAEs, whether related or 
not related to study drug, must be collected, including those thought to be associated with 
protocol-specified procedures. All SAEs must be collected that occur during the screening period 


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Protocol Version Date: 10.26.2018 
 
31 
and within 30 days of discontinuing dosing. If applicable, SAEs must be collected that relate to 
any later protocol-specific procedure (such as follow-up skin biopsy). 
The investigator should report any SAE occurring after these time periods that is believed to be 
related to study drug or protocol-specified procedure.  
An SAE report should be completed for any event where doubt exists regarding its status of 
seriousness.  
If the investigator believes that an SAE is not related to study drug, 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 Report Form. 
SAEs, whether related or unrelated to the study drug, and pregnancies must be reported to BMS 
within 24 hours of awareness of the event. SAEs must be recorded on the FDA MedWatch Form 
3500A; Pregnancies on a Pregnancy Surveillance Form. 
SAE Email Address: 
 
SAE Fax Number: 
 
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.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information 
becomes available, a follow-up SAE report should be sent within 24 hours to the BMS (or 
designee) using the same procedure used for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
 
7.10.1 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 
.  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. 
7.10.2 Pregnancy 
 


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32 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 5 half-lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner. (eg, dose tapering if necessary for 
participant).  
The investigator must immediately notify 
 of this event via the 
Pregnancy Surveillance Form within 24 hours and in accordance with SAE reporting procedures.  
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant unless contraindicated by pregnancy (eg, x-ray studies). Other appropriate pregnancy 
follow-up procedures should be considered if indicated. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form [provided upon request from BMS] 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. In 
order for Sponsor or designee to collect any pregnancy surveillance information from the female 
partner, the female partner must sign an informed consent form for disclosure of this information.  
 
7.11 
Expedited Reporting to the Food and Drug Administration (FDA)  
 
The Overall PI, as study sponsor, will be responsible for all communications with the FDA. The 
Overall PI will report to the FDA, regardless of the site of occurrence, any serious adverse event 
that meets the FDA’s criteria for expedited reporting following the reporting requirements and 
timelines set by the FDA. 
 
7.12 
Expedited Reporting to Hospital Risk Management 
  
Participating investigators will report to their local Risk Management office any participant 
safety reports or sentinel events that require reporting according to institutional policy.  
 
7.13 
Routine Adverse Event Reporting 
 
All Adverse Events must be reported in routine study data submissions to the Overall PI on the 
toxicity case report forms.  AEs reported through expedited processes (e.g., reported to the 
IRB, FDA, etc.) must also be reported in routine study data submissions. 
 
 
 
8 
PHARMACEUTICAL AGENT INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational or other agents 
administered in this study can be found in Section 7.7. 
 


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Protocol Version Date: 10.26.2018 
 
33 
8.1 
Mechanism of Action.   
 
Apixaban is a selective inhibitor of FXa. It does not require antithrombin III for antithrombotic 
activity. Apixaban inhibits free and clot-bound FXa, and prothrombinase activity. Apixaban has 
no direct effect on platelet aggregation, but indirectly inhibits platelet aggregation induced by 
thrombin. By inhibiting FXa, apixaban decreases thrombin generation and thrombus 
development. 
 
8.2 
Pharmacodynamics 
 
As a result of FXa inhibition, apixaban prolongs clotting tests such as prothrombin time (PT), 
INR, and activated partial thromboplastin time (aPTT). Changes observed in these clotting tests 
at the expected therapeutic dose, however, are small, subject to a high degree of variability, and 
not useful in monitoring the anticoagulation effect of apixaban.  
 
The Rotachrom® Heparin chromogenic assay was used to measure the effect of apixaban on 
FXa activity in humans during the apixaban development program. A concentration dependent 
increase in anti-FXa activity was observed in the dose range tested and was similar in healthy 
subjects and patients with AF.  This test is not recommended for assessing the anticoagulant 
effect of apixaban. 
 
8.3 
Specific Populations 
 
Renal impairment:  
Anti-FXa activity adjusted for exposure to apixaban was similar across renal function 
categories. 
 
Hepatic impairment:  
Changes in anti-FXa activity were similar in patients with mild-to-moderate hepatic 
impairment and healthy subjects. However, in patients with moderate hepatic 
impairment, there is no clear understanding of the impact of this degree of hepatic 
function impairment on the coagulation cascade and its relationship to efficacy and 
bleeding. Patients with severe hepatic impairment were not studied. 
 
Cardiac Electrophysiology 
Apixaban has no effect on the QTc interval in humans at doses up to 50 mg. 
 
8.4 
Pharmacokinetics 
 
Apixaban demonstrates linear pharmacokinetics with dose-proportional increases in 
exposure for oral doses up to 10 mg. 
 
Absorption 
The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg of 
APIXABAN. Food does not affect the bioavailability of apixaban. Maximum 
concentrations (Cmax) of apixaban appear 3 to 4 hours after oral administration of 


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Protocol Version Date: 10.26.2018 
 
34 
APIXABAN. At doses ≥25 mg, apixaban displays dissolution-limited absorption with 
decreased bioavailability. Following oral administration of 10 mg of apixaban as 2 
crushed 5 mg tablets suspended in 30 mL of water, exposure was similar to that after oral 
administration of 2 intact 5 mg tablets. Following oral administration of 10 mg of 
apixaban as 2 crushed 5 mg tablets mixed with 30 g of applesauce, the Cmax and AUC 
were 20% and 16% lower, respectively, when compared to administration of 2 intact 5 
mg tablets. Following administration of a crushed 5 mg APIXABAN tablet that was 
suspended in 60 mL D5W and delivered through a nasogastric tube, exposure was similar 
to that seen in other clinical trials involving healthy volunteers receiving a single oral 5 
mg tablet dose. 
 
Distribution 
Plasma protein binding in humans is approximately 87%. The volume of distribution 
Vss) is approximately 21 liters. 
 
Metabolism 
 
Approximately 25% of an orally administered apixaban dose is recovered in urine and 
feces as metabolites. Apixaban is metabolized mainly via CYP3A4 with minor 
contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. O-demethylation and 
hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation. 
Unchanged apixaban is the major drug-related component in human plasma; there are 
no active circulating metabolites. 
 
Elimination 
 
Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 27% 
of total clearance. Biliary and direct intestinal excretion contributes to elimination of 
apixaban in the feces. Apixaban has a total clearance of approximately 3.3 L/hour and an 
apparent half-life of approximately 12 hours following oral administration. Apixaban is a 
substrate of transport proteins: P-gp and breast cancer resistance protein. 
 
Drug Interaction Studies 
 
In vitro  
Apixaban studies at concentrations significantly greater than therapeutic exposures, no 
inhibitory effect on the activity of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, 
CYP2D6, CYP3A4/5, or CYP2C19, nor induction effect on the activity of CYP1A2, 
CYP2B6, or CYP3A4/5 were observed. Therefore, apixaban is not expected to alter the 
metabolic clearance of co-administered drugs that are metabolized by these enzymes. 
Apixaban is not a significant inhibitor of P-gp. 
 
In dedicated studies conducted in healthy subjects, famotidine, atenolol, prasugrel, and 
enoxaparin did not meaningfully alter the pharmacokinetics of apixaban. In studies 
conducted in healthy subjects, apixaban did not meaningfully alter the pharmacokinetics 
of digoxin, naproxen, atenolol, prasugrel, or acetylsalicylic acid. 


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35 
 
Specific Populations 
 
Gender: A study in healthy subjects comparing the pharmacokinetics in males and 
females showed no meaningful difference. 
 
Race: The results across pharmacokinetic studies in normal subjects showed no 
differences in apixaban pharmacokinetics among White/Caucasian, Asian, and Black/ 
African American subjects. No dose adjustment is required based on race/ethnicity. 
 
Hemodialysis in ESRD subjects: Systemic exposure to apixaban administered as a 
single 5 mg dose in ESRD subjects dosed immediately after the completion of a 4-hour 
hemodialysis session (post-dialysis) is 36% higher when compared to subjects with 
normal renal function. The systemic exposure to apixaban administered 2 hours prior to a 
4-hour hemodialysis session with a dialysate flow rate of 500 mL/min and a blood flow 
rate in the range of 350 to 500 mL/min is 17% higher compared to those with normal 
renal function. The dialysis clearance of apixaban is approximately 18 mL/min. The 
systemic exposure of apixaban is 14% lower on dialysis when compared to not on 
dialysis. Protein binding was similar (92%-94%) between healthy controls and ESRD 
subjects during the on-dialysis and off-dialysis periods. 
 
It is important to note that clinical efficacy and safety studies with ELIQUIS did not 
enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD 
maintained on intermittent hemodialysis, administration of ELIQUIS at the usually 
recommended dose [see Dosage and Administration (2.1)] will result in concentrations of 
apixaban and pharmacodynamic activity similar to those observed in the ARISTOTLE 
study [see Clinical Pharmacology (12.3)]. It is not known whether these concentrations 
will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis 
as was seen in ARISTOTLE 
 
8.5 
Pharmaceutical Section for Apixaban:  
 
Please refer to package insert for additional details. 
 
https://www.accessdata.fda.gov/drugsatfda docs/label/2012/202155s000lbl.pdf 
 
8.5.1 
Description 
 
The chemical name is: (-)-cis-2-(2-chorophnyl-5,7-dihydroxy-8-(4R-3S-hydroxy-1-
methyl) piperidinyl-4H-1benzopyran-4-one,hydrochloride. Flavopiridol is also known as 
HMR 1275 and is a synthetic flavone. The molecular formula is C21H20CINO3 HCL. 
The molecular weight is 438.29.  
 
Apixaban displays prolonged absorption. Thus, despite a short clearance half-life of 
about 6 hours, the apparent half-life during repeat dosing is about 12 hours, which allows 


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Protocol Version Date: 10.26.2018 
 
36 
twice-daily dosing to provide effective anticoagulation, but it also means that when the 
drug is stopped for surgery, anticoagulation persists for at least a day.  
 
Absorption  
The absolute bioavailability of apixaban is approximately 50% for doses up to 10 mg of 
ELIQUIS. Food does not affect the bioavailability of apixaban. Maximum concentrations 
(Cmax) of apixaban appear 3 to 4 hours after oral administration of ELIQUIS. Apixaban 
is absorbed throughout the gastrointestinal tract with the distal small bowel and ascending 
colon contributing about 55% of apixaban absorption. Apixaban demonstrates linear 
pharmacokinetics with dose-proportional increases in exposure for oral doses up to 10 
mg. At doses ≥25 mg, apixaban displays dissolution-limited absorption with decreased 
bioavailability.  
 
Distribution  
Plasma protein binding in humans is approximately 87%. The volume of distribution 
(Vss) is approximately 21 liters.  


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Protocol Version Date: 10.26.2018 
 
37 
Metabolism  
Approximately 25% of an orally administered apixaban dose is recovered in urine and 
feces as metabolites. Apixaban is metabolized mainly via CYP3A4 with minor 
contributions from CYP1A2, 2C8, 2C9, 2C19, and 2J2. O-demethylation and 
hydroxylation at the 3-oxopiperidinyl moiety are the major sites of biotransformation.  
Unchanged apixaban is the major drug-related component in human plasma; there are no 
active circulating metabolites.  
 
Elimination  
Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 27% 
of total clearance. Biliary and direct intestinal excretion contributes to elimination of 
apixaban in the feces.  
 
Following intravenous administration, apixaban is eliminated with a dominant half-life of 
~ 5 hours. Following oral administration, the apparent half-life is ~12 hours because of 
prolonged absorption.  
 
Apixaban is a substrate of transport proteins: P-gp and breast cancer resistance protein. 
 
8.5.2 
Form 
 
Apixaban is available in 2.5 mg, yellow, round, biconvex, film-coated tablets with “893” 
debossed on one side and “2½” on the other side and 5 mg, pink, oval-shaped, biconvex, 
film-coated tablets with “894” debossed on one side and “5” on the other side 
 
8.5.3 
Storage and Stability 
 
Store at 20°C to 25°C (68°F-77°F); excursions permitted between 15°C and 30°C 
(59°F-86°F) [see USP Controlled Room Temperature]. 
 
8.5.4 
Compatibility 
 
N/A 
 
8.5.5 
Handling 
 
Qualified personnel, familiar with procedures that minimize undue exposure to 
themselves and the environment, should undertake the preparation, handling, and safe 
disposal of the agent in a self-contained and protective environment.  
 
8.5.6 
Availability 
 
Apixaban is commercially available and will be supplied by Bristol-Myers Squibb 
 
8.5.7 
Preparation 
 


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38 
For patients who are unable to swallow whole tablets, 5 mg ELIQUIS tablets 
may be crushed and suspended in water, 5% dextrose in water (D5W), or apple juice, 
or mixed with applesauce and promptly administered orally [see U.S. Prescribing 
Information Clinical Pharmacology(12.3)].  
 
Alternatively, ELIQUIS tablets may be crushed and suspended in 60 mL of water 
or D5W and promptly delivered through a nasogastric tube [see U.S. Prescribing 
Information, Clinical Pharmacology (12.3)]. 
 
Crushed ELIQUIS tablets are stable in water, D5W, apple juice, and applesauce for up 
to 4 hours. 
 
8.5.8 
Administration 
 
NOTE:  These instructions must be consistent with protocol section 5: TREATMENT 
AND/OR IMAGING PLAN. 
 
Apixaban will be initiated at 10 mg twice a day orally for the first 7 days.  After 7 days, 
the dose of apixaban will be changed to 5 mg twice daily.    This dosing regimen is the 
FDA approved dose per package insert.   Per FDA approved guidelines, there is no 
requirements for dose modifications once patients meets inclusion and exclusion criteria. 
 
For patients who are unable to swallow whole tablets, 5 mg APIXABAN tablets may be 
crushed and suspended in water, 5% dextrose in water (D5W), or apple juice, or mixed 
with applesauce and promptly administered orally.  
 
Alternatively, APIXABAN tablets may be crushed and suspended in 60 mL of water or 
D5W and promptly delivered through a nasogastric tube.  
 
Crushed APIXABAN tablets are stable in water, D5W, apple juice, and applesauce for up 
to 4 hours. 
 
No hydration or pre-medications are required prior to administration of apixaban.  There 
are no dietary restrictions when taking apixaban.  There are no specific precautions 
necessary when administering apixaban. 
 
 
8.5.9 
Ordering 
 
Commercially available apixaban will be ordered via study drug order form supplied by 
Bristol-Myers Squibb. Please allow up to 5 business days for processing.   
 
8.5.10 Accountability 
 
 
The investigator, or a responsible party designated by the investigator, should maintain a 


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39 
careful record of the inventory and disposition of the agent using the NCI Drug 
Accountability Record Form (DARF) or another comparable drug accountability form.  
(See the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
 
8.5.11 Destruction and Return 
 
Per institutional destruction policy. Returns are not accepted by BMS.  
 
9 
BIOMARKER, CORRELATIVE, AND SPECIAL STUDIES:  
 
None 
 


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Protocol Version Date: 10.26.2018 
 
40 
10 
STUDY CALENDAR 
 
Baseline evaluations are to be conducted within 7 days prior to start of protocol therapy, unless 
otherwise noted. Assessments must be performed prior to administration of any study agent.  
 
Procedure 
Day -7 to 
Day 1: 
Screening 
and  
Enrollment 
 
Day 1: 
Initiation 
of 
Therapy10 
Daily for Day 2 
through and 
including Day 
of Discharge 
30 Day Follow-
up  
(+ 5 days) 11 
90 Day Follow-
up for isolated 
HITT 
(+ 5 days) 11 
30 Day after 
discontinuation 
of all treatment 
(+ 5 days) 11 
Unschedul
ed Visits 12 
Informed Consent 
x 
 
 
 
 
 
 
Demographics 
x 
 
 
 
 
 
 
Medical History 
x 
 
 
 
 
 
 
Physical Exam 
x 
x 
 
x 
X 
X 
X 
Height14  
x 
 
 
 
 
 
 
Weight 
x 
x 
 
 
 
 
 
Clinical Assessment 
for signs and 
symptoms of TEC or 
other significant 
findings1 
x 
x  
x 
x 
X 
X 
X 
Vital Signs 
(temperature, pulse, 
respirations, blood 
pressure, oxygen 
saturation) 
x 
x 
x 
x 
X 
X 
X 
ECOG Performance 
Status 
x 
x 
 
 
 
 
 
CBC w/ Platelets2 
x 
x 
x 
x 
X 
X 
X 
Serum Chemistry 
Panel3 
x 
x 
x 
x 
X 
X 
X 
Urine or Serum HCG 
(as appropriate)4 
x 
 
 
 
 
 
 
Hepatic Profile5 
x 
x 
 
 
 
 
X 
HIT Confirmatory 
Test6 
x 
 
 
 
 
 
 
Lower Extremity Non 
-invasive 7 
X 
 
 
 
 
Administer Apixaban 
8 
 
x 
x 
 
 
 
 
Coagulation Profile9 
x 
x 
 
x 
x 
 
X 
Concomitant 
Medications 
x 
x 
x 
x 
X 
X 
X 
Adverse Events 
 
X 
x 
x 
X 
X 
X 
Summary of Patient’s 
Clinical Course 
 
 
 
x 
X 
X 
X 
Drug/Diary 
Dispensing13  
 
X 
 
 
 
 
Drug/Diary Return 
 
 
 
x 
x 
 
 
 
1. 
Assessment for any significant findings or any signs and symptoms of TEC. For the purposes of this study, TEC is defined as any 
thromboembolic complication (venous or arterial, and including skin necrosis) 
2. 
CBC (Hemoglobin, hematocrit, WBC with differential, platelet count) 
3. 
Serum Chemistry(Creatinine, BUN, Na, K, CO2, glucose) 
4. 
Acceptable if performed within 7 days prior to initiation of study drug regimen 


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41 
5. 
Hepatic Profile (Total Bilirubin, AST, ALT) 
6. 
HIT Confirmatory Test (HIT Antibody Titers (EIA PF4 or Serotonin-Release Assay [SRA]).  If negative and high clinical suspicion, 
perform SRA if initial test was EIA PF4. 
7. 
LENI: As part of standard of care, all patients with confirmed HIT or high suspicion of HIT undergo lower extremity non invasive testing to 
rule out deep vein thrombosis,  ONE TIME – can be done Day -7 to Day +3.  LENI is not required if the patient is diagnosed with a 
Pulmonary Embolism. 
8. 
Anticoagulant Therapy: Upon clinical diagnosis or high suspicion of HIT, obtain informed consent, determine inclusion/exclusion 
eligibility, enroll subject, and initiate apixaban.   
9. 
Coagulation Profile: PT, INR, PTT  
10. These do not need to be repeated if completed  for screening on day 1.  
11. The procedures will be performed for patients able to come to a follow up clinic visit. Otherwise, subjects will be contacted by phone. 
12. Assessments for unscheduled visits recommended if feasible (ie if patient admitted to outside hospital, these assessments will not be 
possible.  
13. Patients will be dispensed with enough drug prior to discharge to last until the 30 Day Follow Up visit (for HIT) or the 90 Day Follow Up 
visit (for HITT). 
14. Height documented within the month prior to D1 is acceptable 
 
 
11 
MEASUREMENT OF EFFECT 
 
11.1 
Other Response Parameters 
 
11.1.1 Definition of Symptomatic Thromboembolic Complications 
 
Any symptomatic new thrombosis, skin necrosis and/or new thromboembolism, venous and/or 
arterial, in any part of the vascular system (excluding thrombophlebitis), that is clinically 
diagnosed by the investigator and confirmed by objective, diagnostic standards of care, tests is 
defined as TEC.   
• Deep vein thrombosis will be considered confirmed if there is laboratory 
confirmation of a positive venographic study, Doppler results or compression 
ultrasound study.  Events documented by clinical diagnosis alone will be rejected.  In 
cases where the event is a recurrent deep vein thrombosis, clear documentation must 
be provided to demonstrate an interval change from baseline studies.   
• The diagnosis of pulmonary embolism will be confirmed if a positive angiogram, 
computed tomographic angiogram, a completed ventilation-perfusion scan or an 
echocardiogram shows at least two segmental defects without ventilation defects.  In 
cases where the event is a recurrent pulmonary embolism, clear documentation must 
be provided to demonstrate an interval change from baseline studies.   
• Non-DVT/PE thrombosis will be considered confirmed if positive on imaging 
modality. 
• The diagnosis of stroke will be considered confirmed if the patient has a new focal 
neurologic deficit and if the signs and symptoms persist for more than 24 hours.  All 
stroke events will be further classified as hemorrhagic or thrombotic based on clinical 
data.   
• The diagnosis of myocardial infarction will be considered confirmed if the patient 
develops symptoms consistent with an event, accompanied by characteristic changes 
on electrocardiogram and/or elevation of cardiac troponin measured in the serum.   
• The diagnosis of acute arterial insufficiency will be considered confirmed if the 
patient develops symptoms or signs consistent with an event, accompanied by the 
objective determination of arterial insufficiency by pulselessness, arterial Doppler 
ultrasound or angiogram.   


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• The diagnosis of adrenal necrosis (due to presumptive adrenal vein thrombosis) will 
be based upon radiologic evidence of unilateral or bilateral adrenal hemorrhage.  
• The diagnosis of skin necrosis will be considered confirmed if accompanied by 
symptoms or signs consistent with an event, accompanied by skin biopsy, expert 
consultation by a dermatologist and/or objective review of a high-resolution 
photograph of the involved integument by an appropriate specialist.   
• The circumstances of any sudden death will be reviewed by the DF/HCC Data and 
Safety Monitoring Committee (DSMC) per Section 12.2.   
 
11.1.2 Safety 
 
Monitoring of adverse events will be conducted throughout the study, and include new or 
subsequent TEC, major bleeding (in particular fatal, life-threatening, disabling, requiring a 
surgical intervention), further thrombocytopenia, disseminated intravascular coagulopathy, skin 
necrosis, allergic reaction or other events which in the opinion of the investigator are related to 
anticoagulation therapy.  New adverse events, including serious adverse events, will be captured 
on the CRFs including through 30 days after enrollment for isolated HIT and 90 days after 
enrollment for HITT as well as 30 days after discontinuation of all treatment.  New-onset adverse 
events and serious adverse events should be monitored until they are resolved or are clearly 
determined to derive from a patient’s stable or chronic condition or intercurrent illness(es).  
Definitions, documentation, and reporting of adverse events are described in section 7. 
 
11.1.3 Definition of Resolution of Thrombocytopenia 
 
Resolution of Thrombocytopenia will be defined as: 
 
• 
An increase in the platelet count to greater than 100x103/µL in patients with a nadir 
platelet count less than 100x103/ µL or 
• 
A stable, non-declining platelet count for more than 72 hours following the initiation 
of therapy in patients with a nadir platelet count greater than 100x103/ µL. 
 
11.1.4 Definition of Recovery of Thrombocytopenia 
 
Recovery of Thrombocytopenia will be defined as: 
 
• 
An increase in platelet count to greater than 100x103/ µL in patients with a pre-
apixaban platelet count less than 100x103/ µL or 
• 
An increase in the platelet count to 1.5 times the pretreatment value in patients with a 
pre-apixaban platelet count greater than 100x103 µL 
 
 
12 
DATA REPORTING / REGULATORY REQUIREMENTS 
 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 


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(Adverse Events: List and Reporting Requirements). 
 
12.1 
Data Reporting 
 
12.1.1 Method 
 
The Office of Data Quality (ODQ) will collect, manage, and perform quality checks on 
the data for this study. 
 
12.1.2 Responsibility for Data Submission 
 
Investigative sites within DF/HCC or DF/PCC are responsible for submitting data and/or 
data forms to the Office of Data Quality (ODQ) in accordance with DF/HCC policies. 
 
12.2 
Data Safety Monitoring 
 
The DF/HCC Data and Safety Monitoring Committee (DSMC) will review and monitor toxicity 
and accrual data from this study. The committee is composed of medical oncologists, research 
nurses, pharmacists, and biostatisticians with direct experience in cancer clinical research. 
Information that raises any questions about participant safety will be addressed with the Overall 
PI and study team. 
 
The DSMC will review each protocol up to four times a year or more often if required to review 
toxicity and accrual data. Information to be provided to the committee may include: up-to-date 
participant accrual; current dose level information; all grade 2 or higher unexpected adverse 
events that have been reported; summary of all deaths occurring with 30 days of intervention for 
Phase I or II protocols; audit results, and a summary provided by the study team. Other 
information (e.g. scans, laboratory values) will be provided upon request.  
 
 
13 
STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This is a prospective, open label, single center study designed to evaluate the activity and 
tolerability of apixaban for the treatment of hospitalized patients with a confirmed diagnosis of 
isolated heparin induced thrombocytopenia (HIT).  
 
Standard therapy with argatroban in isolated HIT has been associated with an estimated 6-8% 
incidence of new TEC (approximately 7%).  However, the literature also reports mortality rates 
of up to 20% within 30 days of initiation of argatroban therapy.  Furthermore, two recent “real 
world” analyses revealed a much higher risk of death, limb amputation and new thrombosis than 
was reported in prior studies.13,14  
 
The primary endpoint of this study is to evaluate the activity of the oral factor Xa inhibitor, 
apixaban as monotherapy in patients with heparin inducted thrombocytopenia (HIT) and heparin 


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inducted thrombocytopenia with thrombosis (HITT), as defined by the incidence of new 
symptomatic thromboembolic complications (TEC) within 30 days of the time of initiation of 
apixaban. 
 
The proportion of patients with confirmed HIT who are alive without new TEC at day 30 will be 
reported as a binomial proportion.  We will also report the rate of new TEC, as estimated in the 
context of a cumulative incidence model in which death before day 30 in the absence of new 
TEC is treated as a competing risk.   
 
Based on a recent “real world” analysis, where ¼ patients had HITT and ¾ patients had isolated 
HIT, the proportion of patients alive and without TEC was 59% in the HITT group and 66% in 
the isolated HIT group.14  We calculated the expected proportion of patients alive and without 
TEC for this present study based on the proportion of patients and event rates in each group from 
the real world analysis. 
 
A total of 49 patients with a diagnosis or high clinical suspicion for HIT will be enrolled in this 
study using a one-stage design.  We assume a conservative 10% frequency of negative 
confirmatory testing, thus yielding at least 44 patients with confirmed HIT in whom to assess the 
efficacy of this treatment at the conclusion of the trial.  We anticipate that we will accrue and 
complete follow up on all patients within 2 years, based on investigators’ estimates of incident 
cases of HIT at MGH. 
If at least 34 of 44 confirmed HIT patients are alive without new TEC at day 30, we will consider 
the study a success.  The lower bound of the exact 90% confidence interval associated with this 
outcome is 0.65, suggesting that if we observe a 77% success rate, the probability that the true 
but unknown success rate is less than 65% is less than 0.05. We note again that in this 
calculation, both new TEC or death without TEC by day 30 are considered failures.  We will also 
estimate the rate of new TEC at day 30 using the cumulative incidence model, and provide a 
90% confidence interval based on the model estimate of variance. 
A descriptive analysis of the secondary efficacy endpoints will be obtained.   
Exact binomial 90% confidence intervals will be provided.   
Demographic and baseline characteristics will be summarized overall using descriptive statistics 
(mean, median, standard deviation, minimum, and maximum) for continuous variables (e.g., age) 
and counts and percents for categorical variables (e.g., gender or race). 
90% EXACT BINOMIAL CONFIDENCE INTERVALS FOR VARIOUS OBSERVED 
PROPORTIONS OF PATIENTS ALIVE WITHOUT NEW TEC AT DAY 30 
                               
Observed Response 
Rate 
90% CI 


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13.2 
Sample Size, Accrual Rate and Study Duration:  
 
See Section 13.1 above. 
 
Both men and women of all races and ethnic groups are eligible for this trial. It is hoped that the 
accrual targets will resemble the gender, ethnic, and racial composition of the U.S. population as 
closely as possible.   
 
13.3 
Interim Monitoring Plan:  
 
The study will be suspended for toxicity review if 5 or more patients out of the first 15 experience 
major hemorrhagic or thrombotic complications. The following table summarizes the probability 
of suspension given various probabilities of major hemorrhagic or thrombotic complications. 
 
Probability of major hemorrhagic 
or thrombotic complications 
0.13 
0.20 
0.33 
0.40 
Probability of suspension 
0.04 
0.16 
0.60 
0.78 
 
Suspension will also be warranted if death without new TEC occurs in 2 or more of the first 15 
patients. The following table summarizes the probability of suspension given various probabilities 
of death without new TEC. 
 
Probability of death without new 
TEC 
0.10 
0.13 
0.20 
0.25 
Probability of suspension 
0.45 
0.61 
0.83 
0.92 
 
13.4 
Analysis of Primary Endpoints: 
  
See section 13.1 
 
13.5 
Analysis of Secondary Endpoints:  
 
See section 13.1 
 
13.6 
Reporting and Exclusions 
 
13.6.1 Evaluation of Toxicity 
 
All participants will be evaluable for toxicity from the time of their first treatment.  
 
32/44 (73%) 
(60% to 83%) 
34/44 (77%) 
(65% to 87%) 
36/44 (82%) 
(70% to 91%) 


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13.6.2 Evaluation of the Primary Efficacy Endpoint 
 
The full analysis (FA) dataset will include all patients that receive at least one dose of study 
drug.  The per protocol (PP) dataset is a subset of the FA dataset, excluding patients that are 
subsequently ruled out for this diagnosis by negative confirmatory laboratory testing.  The 
primary efficacy analysis will be conducted in the PP data set.  All safety analyses will be 
performed on the FA dataset.  The incidence of new TEC following the initiation of apixaban 
therapy for HIT is the primary efficacy endpoint of this study, however the tolerability and side 
effects will be monitored as well.  
 
 
14 
PUBLICATION PLAN 
 
The results should be made public within 24 months of reaching the end of the study. The end of 
the study is the time point at which the last data items are to be reported, or after the outcome 
data are sufficiently mature for analysis, as defined in the section on Sample Size, Accrual Rate 
and Study Duration. If a report is planned to be published in a peer-reviewed journal, then that 
initial release may be an abstract that meets the requirements of the International Committee of 
Medical Journal Editors. A full report of the outcomes should be made public no later than three 
(3) years after the end of the study.  
 
 


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REFERENCES 
 
1. 
Kelton JG, Warkentin TE. Heparin-induced thrombocytopenia: a historical perspective. Blood 
2008;112:2607-16. 
2. 
Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and 
low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood 2005;106:2710-5. 
3. 
Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis and management. Br J 
Haematol 2003;121:535-55. 
4. 
Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 
1996;101:502-7. 
5. 
Amiral J, Bridey F, Dreyfus M, et al. Platelet factor 4 complexed to heparin is the target for 
antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost 1992;68:95-6. 
6. 
Warkentin TE, Greinacher A. Heparin-induced anaphylactic and anaphylactoid reactions: two 
distinct but overlapping syndromes. Expert Opin Drug Saf 2009;8:129-44. 
7. 
Warkentin TE, Kelton JG. Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 
2001;344:1286-92. 
8. 
Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 
1986;67:27-30. 
9. 
Warkentin TE. Heparin Induced Thrombocytopenia. In: Warkentin TE, ed. Laboratory Testing for 
Heparin-Induced Thrombocytopenia. 3rd ed. New York: Marcel Dekker, Inc; 2004:271-311. 
10. 
Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced 
thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of 
Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e495S-530S. 
11. 
Lewis BE, Wallis DE, Berkowitz SD, et al. Argatroban anticoagulant therapy in patients with 
heparin-induced thrombocytopenia. Circulation 2001;103:1838-43. 
12. 
Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG. Argatroban anticoagulation in patients with 
heparin-induced thrombocytopenia. Arch Intern Med 2003;163:1849-56. 
13. 
Bolbrinker J, Garbe E, Douros A, et al. Immobilization and high platelet count are associated with 
thromboembolic complications in heparin-induced thrombocytopenia. Pharmacoepidemiol Drug Saf 
2017. 
14. 
Kuter DJ, Konkle BA, Hamza TH, et al. Clinical outcomes in a cohort of patients with heparin-
induced thrombocytopenia. Am J Hematol 2017;92:730-8. 
15. 
Warkentin TE, Elavathil LJ, Hayward CP, Johnston MA, Russett JI, Kelton JG. The pathogenesis of 
venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med 
1997;127:804-12. 
16. 
Warkentin TE, Sikov WM, Lillicrap DP. Multicentric warfarin-induced skin necrosis complicating 
heparin-induced thrombocytopenia. Am J Hematol 1999;62:44-8. 
17. 
Salter BS, Weiner MM, Trinh MA, et al. Heparin-Induced Thrombocytopenia: A Comprehensive 
Clinical Review. J Am Coll Cardiol 2016;67:2519-32. 
18. 
Agnelli G, Buller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous 
thromboembolism. N Engl J Med 2013;369:799-808. 
19. 
Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous 
thromboembolism. N Engl J Med 2013;368:699-708. 
20. 
Walenga JM, Prechel M, Hoppensteadt D, et al. Apixaban as an alternate oral anticoagulant for 
the management of patients with heparin-induced thrombocytopenia. Clin Appl Thromb Hemost 
2013;19:482-7. 


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21. 
Sharifi M, Bay C, Vajo Z, Freeman W, Sharifi M, Schwartz F. New oral anticoagulants in the 
treatment of heparin-induced thrombocytopenia. Thromb Res 2015;135:607-9. 
22. 
Larsen PB, Jorgensen M, Friis-Hansen L, Ingeberg S. Apixaban used for the management of 
heparin-induced thrombocytopenia in a 72-year-old woman with lung cancer. Clin Case Rep 2015;3:987-
9. 
23. 
Frost C, Wang J, Nepal S, et al. Apixaban, an oral, direct factor Xa inhibitor: single dose safety, 
pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br J Clin Pharmacol 
2013;75:476-87. 
24. 
Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease: Antithrombotic 
Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based 
Clinical Practice Guidelines. Chest 2012;141:e419S-94S. 
 
 
 


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APPENDIX A 
PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but ambulatory and 
able to carry out work of a light or sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-care, but unable to carry out 
any work activities.  Up and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally confined to 
bed or chair. 
5 
Dead. 
 
 
 


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APPENDIX B 
INFORMATION ON POSSIBLE DRUG INTERACTIONS 
 
Information on Possible Interactions with Other Agents for Patients and Their Caregivers 
and Non-Study Healthcare Team 
 
The participant ____________________________ is enrolled on a clinical trial using the agent 
APIXABAN.  This clinical trial is a Principal Investigator initiated study.  This form is 
addressed to the participant, but includes important information for others who care for this 
participant.  
 
Apixaban may interact with other drugs.  Because of this, it is very important to tell your study 
doctors about all of your medicine before you start this study.  It is also very important to tell 
them if you stop taking any regular medicine, or if you start taking a new medicine while you 
take part in this study.  When you talk about your medicine with your study doctor, include 
medicine you buy without a prescription at the drug store (over-the-counter remedy), or herbal 
supplements such as St. John’s wort.  
 
Many health care prescribers can write prescriptions.  You must also tell your other prescribers 
(doctors, physicians’ assistants or nurse practitioners) that you are taking part in a clinical trial. 
These are the things that you and they need to know:  
 
Apixaban interacts with drugs that work certain specific enzyme(s) in your liver.  
 
• The enzymes in question are CYP3A4 and P-glycoprotein. Inhibitors of CYP3A4 and P-gp 
increase exposure to apixaban and could result in high levels of the active drug, 
increasing the chance of harmful side effects such as the risk of bleeding. Inducers of 
CYP3A4 and P-gp decrease exposure to apixaban and could reduce the effectiveness of 
the drug which could thereby increase the risk of stroke and other thromboembolic 
events. 
• Therefore, if you are on any medication that involves CYP3A4 and P-glycoprotein, 
apixaban must be discontinued.   
• You and healthcare providers who prescribe drugs for you must be careful about adding or 
removing any drug in this category.  
• Before you start the study, your study doctor will work with your regular prescriber to 
switch any medicines that are considered “strong inducers/inhibitors or substrates of 
CYP3A4 and P-glycoprotein  
• Your prescribers should look at this web site 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx or consult a medical reference to see 
if any medicine they want to prescribe is on a list of drugs to avoid.   
• Please be very careful!  Over-the-counter drugs have a brand name on the label—it’s 
usually big and catches your eye.  They also have a generic name—it’s usually small and 
located above or below the brand name, and printed in the ingredient list.  Find the 
generic name and determine, with the pharmacist’s help, whether there could be an 
adverse interaction.   
• Be careful:  


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o If you take acetaminophen regularly:  You should not take more than 4 grams a 
day if you are an adult or 2.4 grams a day if you are older than 65 years of age.  
Read labels carefully!  Acetaminophen is an ingredient in many medicines for 
pain, flu, and cold. 
o If you take herbal medicine regularly:  You should not take St. John’s wort while 
you are taking Apixaban. 
 
Other medicines can be a problem with your study drugs.  
 
• You should check with your doctor or pharmacist whenever you need to use an 
over-the-counter medicine or herbal supplement.  
 
• Your regular prescriber should check a medical reference or call your study 
doctor before prescribing any new medicine for you.  Your study doctor’s name is  
 
 
Dr. Rachel Rosovsky and she can be contacted at 617-726-2000. 
 
 
 


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APPENDIX C 
APIXABAN PACKAGE INSERT 
 
https://www.accessdata.fda.gov/drugsatfda docs/label/2012/202155s000lbl.pdf 
 


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APPENDIX D 
 
Transition to apixaban from other anticoagulants: taken from package insert 
 
2.4 Converting from or to ELIQUIS 
 
Switching from warfarin to ELIQUIS: Warfarin should be discontinued and ELIQUIS started 
when the international normalized ratio (INR) is below 2.0. 
 
Switching from anticoagulants other than warfarin (oral or parenteral) to ELIQUIS: 
Discontinue the anticoagulant other than warfarin and begin taking ELIQUIS at the usual 
time of the next dose of the anticoagulant other than warfarin. 
 
 
 
 
 


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APPENDIX E 
 
Child-Pugh B and C) Definition 
 
Five clinical features are used to assess the severity of liver disease: 1) grade of hepatic 
encephalopathy, 2) degree of ascites 3) total bilirubin level, 4) serum albumin, and 5) 
prothrombin time prolongation (measured as INR). The total point score is then used to 
determine each patient’s Child-Pugh class.  
 
Factor 
1 point 
2 points 
3 points 
Encephalopathy 
None 
Altered mood/confusion or  
inappropriate behavior, 
impending stupor, somnolence 
Markedly confused, stuporous 
but arousable or 
Comatose/unresponsive 
Ascites 
Absent 
Slight 
Moderate 
Bilirubin (mg/dL) 
 <2 
2-3 
>3 
Albumin (g/dL) 
>3.5 
2.8-3.5 
<2.8 
Prothrombin time 
prolongation (INR) 
<1.7 
1.7-2.3 
>2.3 
 
 
Child Pugh Interpretation 
 
5-6 points 
Child class A 
7-9 points 
Child class B 
10-15 points 
Child class C