Conditions: Cerebral Vein Thrombosis Deep Vein Thrombosis Hematopoietic and Lymphoid Cell Neoplasm Malignant Solid Neoplasm Metastatic Malignant Solid Neoplasm Pulmonary Embolism Splanchnic Vein Thrombosis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 370
Healthy volunteers: no

Brief summary:
This randomized phase III trial studies the best dose of apixaban and how well it works in preventing secondary cancer related venous thrombosis in cancer patients who have completed anticoagulation therapy. Apixaban may help in prevention by blocking some of the enzymes needed for venous thrombosis.

Detailed description:
PRIMARY OBJECTIVE:

I. Any episode of major bleeding including fatal bleeding or clinically relevant non-major bleeding.

SECONDARY OBJECTIVES:

I. The proportion of patients who experienced at least one such bleeding event within 6 months of beginning treatment.

II. Venous thromboembolism (VTE) recurrence including deep vein thrombosis (DVT), pulmonary embolism (PE), fatal PE, or arterial thromboembolism.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP I: Patients receive lower dose apixaban orally (PO) twice daily (BID) for 365 days.

GROUP II: Patients receive higher dose apixaban PO BID for 365 days.

After completion of study treatment, patients are followed up for 30 days.

Arms:
arm 1: Patients receive lower dose apixaban PO BID for 365 days. arm 2: Patients receive higher dose apixaban PO BID for 365 days.

Interventions: intervention 1: Apixaban
Intervention descriptions: intervention 1: Given PO

Protocol document:
Prot_SAP_ICF_000.pdf: 
  
 ACCRU-SC-1601 
  
Academic and Community Cancer Research United (ACCRU) 
 
A Phase III, Randomized, Controlled, Double-Blind Study Evaluating the Safety of Two Doses of 
Apixaban for Secondary Prevention of Cancer Related Venous Thrombosis in Subjects Who Have 
Completed at Least Six Months of Anticoagulation Therapy 
 
For any communications regarding this protocol,  
please contact the protocol resource person on the following page. 
 
Study Chairs 
 
ACCRU: 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
  
 
 
   
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
             Study Cochair: 
 
 
                                        Statistician:  
   
 
  
 
  
 
  
  
 
  
 
  
 
 
  
  
 
 
Drug Availability  
Drug Company Supplied:  Apixaban (Eliquis®) – IND #134645 
 
√ Study contributor(s) not responsible for patient care. 
 
Research Coordinating Center 
 
 
 
 
Document History 
Effective Date 
Pre-activation ACCRU 
December 23, 2016 
Activation ACCRU – Amendment 1 
July 14, 2017  


Amendment 1 
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ACCRU-SC-1601 
 
 
Index 
 
 
Schema 
  1.0 
Background 
  2.0 
Goals 
  3.0 
Patient Eligibility 
  4.0 
Test Schedule 
  5.0  
Stratification Factors   
  6.0 
Registration/Randomization Procedures 
  7.0 
Protocol Treatment 
  8.0 
Dosage Modification Based on Adverse Events  
  9.0 
Ancillary Treatment/Supportive Care 
10.0 
Adverse Event (AE) Reporting and Monitoring  
11.0 
Treatment Evaluation Using RECIST Guideline 
12.0 
Descriptive Factors 
13.0 
Treatment/Follow-up Decision at Evaluation of Patient  
14.0 
Body Fluid Biospecimens 
15.0 
Drug Information 
16.0 
Statistical Considerations and Methodology 
17.0 
Pathology Considerations/Tissue Biospecimens 
18.0 
Records and Data Collection Procedures 
19.0 
Budget 
20.0 
References 
Appendix I - Consent Form 
Appendix II - Strong CYP3A4 Inhibitors 
Appendix III - Khorana Score  
Appendix IV- Non CTCAE Bleeding Grading Scale 
Appendix V- Phone Contact Sheet    
Appendix VI - Patient Instructions    
Appendix VII - Patient Compliance Information 
 
  
  
 


Amendment 1 
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Schema 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Cycle = 30 days 
 
 
Generic name:    Apixaban  
Brand name(s):  Eliquis® 
Availability:   Biologics, Inc. 
  
 
  
Apixaban 5 mg twice daily  
for a total of 12 months (365 days)  
  
  
Apixaban 2.5 mg twice daily  
for a total of 12 months (365 days) 
  
  
Unacceptable adverse events or patient 
refusal at any time →  Off Study  
 
Off Study 
 
Randomization   


Amendment 1 
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ACCRU-SC-1601 
 
1.0 
Background   
  
1.1 
Treatment  
 
Active cancer is associated with a markedly increased risk of both incident and recurrent 
venous thromboembolism.  The rate of recurrence has been estimated to be between 2 to 
9 fold higher compared to patients without cancer (1-8).  For those cancer patients who 
suffer a VTE recurrence, the risk of death is increased 3-fold particularly if the recurrent 
event is a pulmonary embolism (9).  In keeping with these data, current guidelines 
recommend continued anticoagulation therapy beyond the acute treatment phase of 3 – 6 
months until there is no longer evidence of active cancer (10).  This recommendation 
distinguishes primary treatment (first 3 – 6 months following VTE confirmation) from 
secondary prevention which includes continued treatment beyond 6 months.  These 
guideline recommendations however are based on scant data with an evidence grade 
limited to expert opinion only (Grade 2C)(10).  Of note, patients with cancer also carry 
an increased risk of anticoagulant associated major bleeding (2, 5, 11-14).  Balancing the 
risk of VTE recurrence with the risk of anticoagulant associated major bleeding 
complicates decision making for these patients.  Prolonged anticoagulant therapy may not 
be beneficial for all cancer patients and may indeed provoke harm in some. In the end, 
there are limited data to inform decision making for these patients beyond 6 months of 
therapy.   
 
The LITE investigators randomized 200 cancer patients to receive warfarin or low 
molecular weight heparin (tinzaparin) for 3 months for the acute treatment of VTE (15).  
Thereafter, patients were assessed for an additional 9 months following anticoagulation 
discontinuation.  At three months, 6% of those patients randomized to tinzaparin 
compared to 10% on warfarin suffered an acute VTE recurrence which did not differ 
significantly between treatment allocations.  At 12 months, an additional 7% of patients 
in the tinzaparin group (total of 13%) compared to an additional 16% in the warfarin arm 
(total of 26%) suffered VTE recurrence (p=0.044; risk ratio 0.44; absolute difference 
9.0%, (95% CI -21.7% to -0.7%)).   Major bleeding events were 7% for both groups at 3 
months.  Death occurred in 20% for both groups at 3 months and 47% of both groups at 
12 months.  The high rate of VTE recurrence and death can be appreciated following 
anticoagulation discontinuation.    
 
The DACUS trial assessed cancer patients with first episode of DVT who had been 
treated with low molecular weight heparin (LMWH) for 6 months (16). After 6 months, 
patients underwent duplex ultrasound imaging to assess residual DVT.  Those with 
residual thrombus were then randomly assigned to continue LMWH for an additional 6 
months or to discontinue therapy. For those patients with thrombus resolution (no 
residual thrombus), anticoagulation was discontinued.  They enrolled 347 patients of 
whom 242 patients had residual DVT.  Of these, recurrence occurred in 22 of the 119 
patients (18%) with continued LMWH compared to 27 of 123 patients (22%) who 
stopped therapy.  For those patients without residual thrombus, the recurrence rate was 
low at 2.9% (3/105 patients).   This study suggests that continued anticoagulant therapy 
beyond 6 months based on ultrasound evidence of residual thrombus provides only a 
modest reduction in recurrent venous thromboembolism.  As such, this study does not 
support current guidelines for extending secondary prevention with prolonged LMWH 
therapy beyond 6 months.  Furthermore, decisions based on the presence of residual 
thrombus after acute therapy has not been deemed sufficiently well validated to receive 
guideline endorsement.  Moreover, this information is not sufficient to meet clinical 


Amendment 1 
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ACCRU-SC-1601 
 
equipoise when considering a randomized trial design in cancer patients.  For patients 
with active cancer who have completed 6 month of anticoagulants, there would be little 
appetite for a randomized trial where one group might be randomized to placebo given 
the high rate of VTE recurrence in these patients.   
 
Guideline recommendations for patients with VTE in the setting of an active malignancy 
include extended anticoagulation with LMWH as the preferred anticoagulant regardless 
of the bleeding risk (10).  Anticoagulants are often continued until there is no evidence of 
active malignancy defined as any evidence of cancer on cross-sectional imaging or any 
cancer related treatment (surgery, radiation, or chemotherapy) within the past 6 months.  
Chronic LMWH therapy however has several disadvantages.  First, LMWH is given by 
subcutaneous injections which may be painful and cause considerable local ecchymoses 
and hematomas.  Second, the cost of LMWH may be prohibitive.  For individuals without 
insurance, this can be more than $100 USD daily.  Because this treatment is often given 
for months on end, health-care costs for medications alone can be thousands of dollars.  
Third, thrombocytopenia associated with the cancer or cancer treatments limit its use and 
raise clinical concerns regarding possible heparin induced thrombocytopenia.  Fourth, 
there is neither a specific nor effective proven antidote should the patient develop 
bleeding complications.  Fifth, renal failure which can be common with cancer or cancer 
related treatment limits the use of this medication.   For these combined reasons, an 
alternative anticoagulation therapy for patients with cancer associated VTE would be 
extremely attractive. 
 
1.2 
Investigational Agent 
 
Apixaban (Eliquis) is an oral direct factor Xa inhibitor which impairs coagulation by 
inhibiting the conversion of prothrombin to thrombin.  It does not require antithrombin 
for antithrombotic activity and inhibits both free and clot-bound FXa.  Apixaban has a 
half-life of about 12 hours and thus is dosed twice-daily.  Bioavailability is approximately 
50% after oral dosing with maximum concentrations at 4 hours post ingestion.  The 
pharmacokinetics are linear and plasma protein binding in humans is high at 
approximately 87% with a volume of distribution of approximately 21 liters.  Apixaban is 
metabolized in the liver mainly via the CYP3A4 pathway.  Renal excretion accounts for 
about 27% of total clearance.  Approximately 25% of the drug is eliminated in the feces. 
This drug is not dialyzable due to its high plasma protein binding. (“The dialysis 
clearance of apixaban is approximately 18 mL/min resulting in a 14% decrease in 
exposure due to hemodialysis compared to off-dialysis period.”)  Apixaban is currently 
FDA approved for the treatment of DVT and PE, and for the reduction in the risk of 
recurrent DVT and PE following initial therapy, for the prophylaxis of deep vein 
thrombosis (DVT), which may lead to pulmonary embolism (PE), in patients who have 
undergone hip or knee replacement surgery and reducing the risk of stroke/systemic 
embolism in the setting of non-valvular atrial fibrillation. 
 
1.3 
Clinical Data to Date 
 
The AMPLIFY investigators randomized 5395 patients with acute VTE to either 
apixaban (10 mg twice daily for 7 days followed by 5 mg twice daily for 6 months) or 
enoxaparin/warfarin (17).  The primary efficacy outcome, recurrent symptomatic VTE or 
death related to VTE, occurred in 2.3% in the apixaban group compared to 2.7% in the 
conventional-therapy group.  From an efficacy standpoint, apixaban was therefore 
deemed non-inferior to standard anticoagulant therapy.  Both major bleeding and the 


Amendment 1 
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ACCRU-SC-1601 
 
composite of major plus non-major yet clinically relevant bleeding were significantly 
lower for patients receiving apixaban.  The AMPLIFY-EXT investigators randomized 
2482 patients with VTE who had recently completed 6 – 12 months of anticoagulation to 
receive one of two doses of apixaban (5 mg twice daily or 2.5 mg twice daily) or placebo 
for an additional 12 months.  Both apixaban doses reduced recurrent VTE without 
increasing major bleeding compared to placebo (18).  
 
There are now 10 studies comparing direct oral factor inhibitors with conventional 
anticoagulation for treatment of patients with VTE (19).  A recent metaanalysis was 
performed to assess the safety and efficacy of direct factor inhibitors in cancer patients 
with VTE by combining all of the cancer patients from each study.  Patients from 6 of the 
10 studies were included (dabigatran 2 studies, rivaroxaban 2 studies, edoxaban 1 study, 
and apixaban 1 study).  Combined there were 1,132 cancer patients evaluated.  Based on 
each of the studies included, the comparator was conventional anticoagulation with 
heparin and warfarin.  Venous thromboembolism occurred in 3.9% of patients treated 
with a direct factor inhibitor and 6.0% in those assigned to conventional therapy.  These 
rates did not differ statistically.  Major bleeding occurred in 3.2% of patients treated with 
a direct factor inhibitor and 4.2% in those assigned to conventional therapy which also 
did not differ.  Based on these data, direct factor inhibitor therapy appears both effective 
and safe compared to conventional therapy in cancer patients.     
 
Despite these trial results, apixaban is not currently recommended for cancer related VTE 
treatment or secondary prevention for several reasons.  First, there are limited data 
supporting the use of apixaban in cancer patients with no trials specifically designed to 
evaluate its utility in cancer patients.  In the AMPLIFY treatment trial, only 2.65% (143 
patients) had underlying cancer as a risk factor with only 66 patients with active cancer in 
the apixaban arm.  In the AMPLIFY Extend trial, only 42 patients with active cancer 
were enrolled.  Indeed, the latest guideline regarding cancer associated VTE (10) 
recommended against the use of apixaban (or other direct oral factor inhibitors).  These 
recommendations however were given a very weak strength (Grade 2C) given the lack of 
supporting data.   
 
In the AMPLIFY Extend trial, the comparator was placebo.  This would not likely be 
embraced or even ethical in cancer patients with a VTE history for several reasons.  First, 
opinion leaders in the field often recommend against the use of factor Xa inhibitors in 
cancer patients with VTE (personal communication).  Second, many of our patients are 
concerned about starting a novel anticoagulant for cancer associated VTE treatment in the 
absence of data (personal experience).  Irrespective of this knowledge limitation, the 
hypothesis supporting the use of apixaban in cancer related VTE management remains 
quite attractive.  A current ACCRU trial is investigating the worth of apixaban vs LMWH 
for the treatment of clots in cancer patients, for 6 months. 
 
In order to gain guideline endorsement for prolonged secondary prevention, apixaban 
must be assessed in a randomized controlled trial setting.   The current standard of care 
for these patients is continued LMWH for cancer associated VTE.  The guidelines favor 
extended anticoagulant therapy with no scheduled stop date over shorter predetermined 
durations irrespective of the bleeding risk.   
 
 
 
 


Amendment 1 
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ACCRU-SC-1601 
 
1.4 
Dose Rationale and Risk/Benefits for an Extended Period in Cancer Patients 
 
The AMPLIFY-EXT investigators compared apixaban 5 mg twice daily or 2.5 mg twice 
daily to placebo in 2486 patients who had completed 6 to 12 months of anticoagulant 
therapy for whom there was clinical equipoise regarding continuation or cessation of 
anticoagulant therapy (18).  The vast majority of these patients had no history of active 
cancer.  At 12 months of follow up, recurrent VTE occurred in 1.7% of patients 
randomized to apixaban 2.5 mg and 1.7% for those patients randomized to apixaban 5 mg 
twice daily.  This compared to 8.8% in the placebo arm meeting the criteria for 
superiority for both doses.  The use of apixaban 2.5 mg was associated with a 7.2% 
absolute reduction of VTE recurrence (95% CI, 5.0 to 9.3; P<0.001).  The 5 mg dose was 
associated with a 7% absolute risk reduction (95% CI, 4.9 to 9.1; P<0.001). Major 
bleeding was infrequent and did not differ between treatment groups: apixaban 2.5 mg 
(0.2%), 5 mg (0.1%) and placebo groups (0.5%).  Clinically relevant non-major bleeding 
likewise did not differ between groups: 2.3% (placebo), 3.0% (apixaban 2.5 mg) and 
4.2% (apixaban 5 mg).  Based on these data, both apixaban 2.5 mg or 5 mg twice daily 
are  attractive for extended “secondary prevention” for patients without cancer associated 
VTE.   We hypothesize that apixaban will provide safe and effective secondary 
prevention for patients with cancer associated VTE who have completed 6 months (but 
no more than 12 months) of anticoagulant therapy. 
 
1.5 
General Design  
 
 
This is a multicenter, randomized, double blind, superiority trial for safety.  Participating 
centers will be from the Academic and Community Cancer Research United (ACCRU) 
research consortium.  This research consortium is comprised of more than 80 leading 
academic institutions and community oncology practices in the United States and 
Canada.  The goal of this consortium is to collaborate with industry partners to develop 
and conduct clinical trials in cancer research.     
 
Subjects will be screened at both outpatient clinic visit appointments and during 
hospitalizations using direct referrals or by daily automated screening of the electronic 
medical record.  Interested qualified subjects will be consented and offered participation 
in this trial.  Subjects will be considered for trial participation if they have evidence of 
active cancer and have a history of a documented venous thrombotic event for which they 
have received at least 6 months (but not more than 12 months) of anticoagulant therapy.  
Both the date and location of the original thrombosis will be recorded, as well as the 
anticoagulant used for the original treatment.  After randomization, patients will be 
allocated to receive either apixaban 5 mg twice daily or 2.5 mg twice daily.   Allocation 
to treatment will be done centrally.  Once consent has been obtained, baseline laboratory 
values will be established and subjects will begin treatment and follow-up for 12 months.   
 
The principal safety outcome will be a combined endpoint of major bleeding plus 
clinically relevant non-major bleeding.  All episodes of major bleeding, clinically 
relevant non-major bleeding and deaths will be evaluated by a central, blinded, 
independent adjudication committee. Adjudication results will be the basis for the final 
analyses. An independent data and safety monitoring board (DSMB) will monitor the 
patients’ safety and give recommendations to the executive committee.  
 
 
 


Amendment 1 
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2.0 
Goals    
 
 
2.1 
Primary Safety Endpoint 
 
2.11    The primary safety endpoint will include the combined endpoint: any episode of 
major bleeding including fatal bleeding or clinically relevant non major bleeding.  
In particular, we will consider the proportion of patients who experience at least 
one such bleeding event within 12 months of beginning treatment.  The following 
criteria will be used to confirm and categorize a bleeding episode: 
 
• 
Major bleeding is defined as overt bleeding plus a hemoglobin decrease of ≥ 
2 g/dL or transfusion of ≥ 2 units of packed red blood cells, or intracranial, 
intraspinal/epidural, intraocular, retroperitoneal, pericardial, intra-articular, 
intramuscular with compartment syndrome or fatal bleeding.  Intracranial 
hemorrhage includes intracerebral (hemorrhagic stroke), subarachnoid, and 
subdural bleeds (21). 
 
• 
Clinically relevant non-major bleeding is defined as overt bleeding not 
meeting the criteria for major bleeding but associated with medical 
intervention, an unscheduled contact with a member of the health care team, 
or temporary cessation of study treatment. 
 
• 
Minor bleeding is defined as overt bleeding that did not meet criteria for 
major bleeding or clinically relevant non-major bleeding. 
 
 
2.2 
Secondary Safety Endpoint  
 
2.21 
The secondary safety endpoint will be the same as the primary safety endpoint,  
 
but in this case we will consider the proportion of patients who experienced at 
least one such bleeding event within 6 months of beginning treatment, as this was 
the primary endpoint in previous studies. 
 
2.3 
Secondary Efficacy Endpoint 
 
2.31  
The secondary efficacy endpoint of this study will be VTE recurrence including 
DVT, PE, fatal PE, or arterial thromboembolism.  The following criteria will be 
used to confirm and categorize a VTE recurrence:  
 
• 
Suspected (recurrent) DVT:  The original DVT must be confirmed by duplex 
ultrasonography, venography, CT, or MRI.  A recurrent DVT must be 
distinguished from the original thrombus by comparing serial imaging 
modalities.  In order to be classified as a recurrent event, there must be new 
filling defects evident on the second study not appreciated on the original 
images or an interval study clearly showing thrombus resolution.    
 
• 
Suspected (recurrent) PE: The original PE must be confirmed by CT, MR, 
conventional pulmonary angiography, or VQ perfusion imaging.  A recurrent 
PE must be distinguished from the original thrombus by comparing serial 
imaging modalities.  In order to be classified as a recurrent event, there must 
be new filling defects evident on the second study not appreciated on the 
original images or an interval study clearly showing thrombus resolution.   


Amendment 1 
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ACCRU-SC-1601 
 
 
• 
Fatal PE:  PE based on objective diagnostic testing, autopsy, or death which 
cannot be attributed to a documented cause and for which PE/DVT cannot be 
ruled out (unexplained death). 
 
• 
Incidental VTE recurrence:  Due to the nature of cancer surveillance related 
imaging, it is anticipated that recurrent venous thrombosis or thrombus 
propagation may be identified.  In order to be classified as an event, the 
thrombus in question must be distinguished from the original thrombus by 
comparing serial imaging modalities.  In order to be classified as a recurrent 
event, there must be new filling defects evident on the second study not 
appreciated on the original images or an interval study clearly showing 
thrombus resolution.   
 
• 
Arterial thromboembolism:  Myocardial infarction (MI), stroke, transient 
ischemic attack (TIA), or peripheral arterial embolism.  
 
3.0 
Patient Eligibility    
 
3.1 
Inclusion Criteria   
 
3.11 
Age ≥18 years. 
 
3.12 
Confirmed acute index  (original venous thrombotic) event: lower extremity or 
upper extremity (jugular, innominate, subclavian, axillary, brachial) DVT, PE, 
splanchnic (hepatic, portal, splenic, mesenteric, renal, gonadal), or cerebral vein 
thrombosis for which the patient has received ≥180 days  (but ≤365 days) of 
anticoagulant therapy prior to registration.  The date, imaging modality, and 
location of index event will be required.   The date of initiation and specific type 
of anticoagulants used will also be required. 
 
3.13 
Active cancer defined as metastatic disease and/or any evidence of cancer on 
cross-sectional or PET imaging, cancer related surgery, chemotherapy or 
radiation therapy within the past 6 months.  Note:  non-melanoma skin cancer 
does not meet the cancer requirement. 
 
3.14 
Life expectancy ≥ 6 months.   
 
3.15 
ECOG Performance Status (PS) of 0, 1, or 2.  (Form is available on the ACCRU 
web site 
  
 
3.16 
The following laboratory values obtained ≤30 days prior to registration.   
• 
Hemoglobin ≥8 g/dL 
• 
Platelet count ≥50,000/mm3 
• 
Alanine aminotransferase (ALT) or Aspartate transaminase (AST) ≤3 x ULN 
• 
Calculated creatinine clearance must be ≥30 ml/min using the Cockcroft-
Gault formula below: 


Amendment 1 
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ACCRU-SC-1601 
 
 
3.17 
Negative serum or urine pregnancy test done ≤7 days prior to registration, 
for women of childbearing potential only. 
Note:  A woman of childbearing potential (WOCBP) is defined as any female 
who has experienced menarche and who has not undergone surgical sterilization 
(hysterectomy or bilateral oophorectomy) and is not postmenopausal. Menopause 
is defined as 12 months of amenorrhea in a woman over age 45 years in the 
absence of other biological or physiological causes.  
 
3.18 
Ability to provide informed written consent. 
 
 
3.19 
Willing to undergo monthly follow-up assessment, either in person at the 
enrolling institution or by telephone (script in Appendix V).  
 
3.2 Exclusion Criteria   
 
3.21 
Any of the following because this study involves an investigational agent whose 
genotoxic, mutagenic and teratogenic effects on the developing fetus and 
newborn are unknown: 
• 
Pregnant women 
• 
Nursing women 
• 
Men or women of childbearing potential who are unwilling to employ 
adequate contraception  
o Note:  Women of child bearing potential must agree to follow instructions 
for method(s) of contraception for the duration of treatment with study 
drug (s) plus 33 days after finishing the last dose.  
o Males who are sexually active with WOCBP must agree to follow 
instructions for method(s) of contraception for the duration of treatment 
with study drug (s) plus 93 days after finishing the last dose.   
o Azoospermic males and WOCBP who are continuously not 
heterosexually active are exempt from contraceptive requirements.  
However they must still undergo pregnancy testing as described in this 
section. 
 
Note:  Investigators shall counsel WOCBP and male subjects who are sexually 
active with WOCBP on the importance of pregnancy prevention and the 
implications of an unexpected pregnancy. Investigators shall advise WOCBP and 
male subjects who are sexually active with WOCBP on the use of highly effective 
methods of contraception. Highly effective methods of contraception have a 
failure rate of < 1% when used consistently and correctly. 
 
At a minimum, subjects must agree to the use of one method of highly effective 
contraception as listed below: 
 
 
Cockcroft-Gault Equation: 
 
Creatinine clearance for males =   
  (140 - age)(weight in kg) 
  
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 
 
Creatinine clearance for females =   
     (140 - age)(weight in kg)___ *(0.85) 
 
 
 
 
 
 
(72)(serum creatinine in mg/dL) 


Amendment 1 
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ACCRU-SC-1601 
 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
 
• 
Male condoms with spermicide 
• 
Hormonal methods of contraception including combined oral contraceptive 
pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) such 
as Mirena® by WOCBP subject or male subject’s WOCBP partner. 
• 
Female partners of male subjects participating in the study may use hormone 
based contraceptives as one of the acceptable methods of contraception since 
they will not be receiving study drug  
• 
IUDs, such as ParaGard® 
• 
Tubal ligation 
• 
Vasectomy. 
• 
Complete Abstinence* 
 
 
*Complete abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all study drugs. 
Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence 
 
3.22 
Active major bleeding.  
 
3.23 
Severe hypersensitivity reaction to apixaban (e.g., anaphylactic reactions). 
 
3.24 
Current use of strong CYP3A4 inducers or inhibitors (see list in appendix II).  
NOTE: Patients may be eligible if they transition to an alternative agent (see 
section 8.1) or are able to stop CYP3A4 inducer or inhibitor.  
 
3.25 
Current use of thienopyridine therapy (clopidogrel, prasugrel, or ticagrelor) that 
will be continued on study. 
 
3.26 
Severe liver disease (known cirrhosis Childs Pugh class B or C),  or active 
hepatitis.  
 
3.27  
Documented venous thromboembolism while on therapeutic anticoagulation 
(“anticoagulation failure”). 
 
3.28 
Mechanical heart valve. 
 
3.28 
Documented hemorrhagic tendencies (e.g., hemophilia). 
 
3.29 
Bacterial endocarditis. 
 
3.30 
Any of the following conditions:   
• 
Intracranial bleeding ≤6 months prior to randomization  
• 
Intraocular bleeding ≤6 months prior to randomization 
• 
Gastrointestinal bleeding and/or endoscopically proven ulcer ≤6 months prior 
to  randomization   
• 
Head trauma or major trauma ≤1 month prior to randomization 
• 
Neurosurgery ≤2 weeks prior to randomization 
• 
Major surgery ≤1 week prior to randomization 
• 
Gross hematuria at the time of randomization 


Amendment 1 
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4.0 
Test Schedule 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1
1
1
1.  ≤30 days prior to registration. 
2.  For women of childbearing potential only.  Negative serum or urine pregnancy test done ≤7 
days prior to registration.  
3.  If it is not feasible for the patient to return to the enrolling center for the monthly 
reassessment, a   detailed history will be obtained by phone using a structured interview (see 
appendix V). 
4. Use the questions in Appendix VII to obtain this information, and document the information 
on the appropriate case report form.  
5. Prior to 1st study drug administration: Appendix VI given to patient and patient educated on 
signs/symptoms of potential thrombosis to monitor and report to study staff.  
 
5.0 
Stratification Factors    
5.1 
Cancer stage:  Residual (intact primary or metastatic) vs. no residual (no evidence of 
disease). 
5.2 
Risk:  High risk vs. lower risk using validated Khorana score  (see appendix III). 
 
Tests and procedures 
 
≤30_days 
prior to 
registration 
(baseline) 
 
Every 30 
days after the 
start of 
treatment 
(± 1 week)3 
 
End of 
treatment 
History and exam (including height and 
weight) 
X 
 
  
ECOG PS 
X 
X  
  
Adverse event assessment3 
X 
X 
X 
Hematology: 
• CBC  
 
 
X1 
 
 
 
 
Chemistry:   
• SGOT (AST) or ALT 
• Creatinine  
 
X1 
 
 
 
Selected concomitant meds3  (see CRF for this 
form) 
X 
X 
X  
Pregnancy test2 
X 
 
 
Patient education regarding signs and 
symptoms of thrombosis (Appendix VI) 
X5 
 
 
Patient Contact (including bleeding assessment, 
see App. IV and V)3 
X 
X 
X 
Patient compliance documentation4 
 
X 
X 


Amendment 1 
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ACCRU-SC-1601 
 
5.3 
Location of initial thrombosis: deep-vein thrombosis (including atypical VTE) vs. 
pulmonary embolism. 
6.0  
Registration/Randomization Procedures 
 
6.1 
Registration Procedures 
 
6.11 
To register a patient, access the ACCRU web page at 
click on “Training Page” and enter the 
registration/randomization application.  The registration/randomization application  
is available 24 hours a day, 7 days a week.  Back up and/or system support contact 
information is available on the Web site.  If unable to access the Web site, call the 
Academic and Community Cancer Research United (ACCRU) Registration Office  
at 
between the hours of 8 a.m. and 4:30 p.m. Central Time (Monday 
through Friday). 
 
The instructions for the registration/randomization application are available by  
using the Help button.  Prior to initiation of protocol study intervention, this process 
must be completed in its entirety and an ACCRU subject ID number must be 
available as noted in the instructions.  It is the responsibility of the individual and 
institution registering the patient to confirm the process has been successfully 
completed prior to release of the study agent.  Patient registration via the 
registration/randomization application can be confirmed in any of the following 
ways: 
• 
Contact the ACCRU Registration Office 
  If the patient was 
fully registered, the ACCRU Registration Office staff can access the 
information from the centralized database and confirm the registration. 
• 
Refer to “Instructions for Remote Registration” in section 
“Finding/Displaying Information about A Registered Subject.” 
 
6.12 
Documentation of IRB approval must be on file in the Registration Office 
before an investigator may register any patients.  
 
In addition to submitting initial IRB approval documents, ongoing IRB approval 
documentation must be on file (no less than annually) at the Registration Office 
(fax: 
).  If the necessary documentation is not submitted in advance 
of attempting patient registration, the registration will not be accepted and the 
patient may not be enrolled in the protocol until the situation is resolved. 
 
When the study has been permanently closed to patient enrollment, submission of 
annual IRB approvals to the Registration Office is no longer necessary. 
 
6.13 
Prior to accepting the registration/randomization, the registration/randomization 
application will verify the following: 
• 
IRB approval at the registering institution 
• 
Patient eligibility 
• 
Existence of a signed consent form 
• 
Existence of a signed authorization for use and disclosure of protected health 
information   
 
 
 


Amendment 1 
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ACCRU-SC-1601 
 
6.14 
Treatment cannot begin prior to registration and must begin ≤30 days after 
registration. 
 
6.15 
Pretreatment tests/procedures (see Section 4.0) must be completed within the 
guidelines specified on the test schedule. 
 
6.16 
Treatment on this protocol must commence at an ACCRU institution under the 
supervision of a health care professional. 
 
6.17 
Study drug is available on site.  
 
6.2 
Randomization Procedures 
 
6.21 
The factors defined in Section 5.0, together with the registering membership, will 
be used as stratification factors. 
 
6.22  
After the patient has been registered into the study, the values of the stratification 
factors will be recorded, and the patient will be assigned to one of the following 
treatment groups using the Pocock and Simon dynamic allocation procedure 
which balances the marginal distributions of the stratification factors between the 
treatment groups (Pocock-Simon).   
• 
Apixaban 2.5 mg twice daily. 
• 
Apixaban 5 mg twice daily.  
 
6.3 
Procedures for Double-Blinding the Treatment Assignment 
 
6.31 
After the treatment assignment has been ascertained by the 
registration/randomization application, the patient’s study medication code 
number will be displayed on the confirmation of registration screen. 
 
6.32 
The data manager/nurse/pharmacist at the patient’s institution must contact the 
ACCRU Registration Office for a code number when additional study product is 
needed for the patient. 
 
6.33 
ACCRU Registration Office personnel will monitor the supply of coded bottles 
at each participating institution and will arrange for the oncology pharmacist to 
send further supplies to the participating institutions as needed. 
 
 


Amendment 1 
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ACCRU-SC-1601 
 
7.0 
Protocol Treatment 
 
 
7.1 
Treatment Schedule  
 
Agent 
Dose Level 
Frequency  
Route 
Apixaban 
2.5 mg 
Twice daily for 12 
months (365 days) 
Oral 
Apixaban 
5 mg    
Twice for daily 12 
months (365 days) 
Oral 
 
*If a dose of apixaban is not taken at the scheduled time, the dose should be taken as soon as 
possible (+/-4 hours of the normal scheduled dose) on the same day and the prescribed dosing 
schedule should be resumed.  If more than 4 hours late, then just wait for the next dose. The dose 
should not be doubled to make up for missed doses.   
 
 
7.11 
Scheduled visits every 30 days +/- 1 week (either in person or by scripted 
telephone interview with a study coordinator) should include a standardized 
assessment for recurrent thromboembolism, bleeding episodes, and adverse 
reactions. Patients should be instructed to report to the clinic immediately (or call 
911/go to the Emergency Room) if they had any bleeding, or symptoms of 
recurrent deep-vein thrombosis, pulmonary embolism, or both. Written patient 
education materials will be provided to each patient outlining signs and 
symptoms to watch for regarding VTE recurrences (appendix VI). All suspected 
episodes of recurrent thrombosis should be investigated with the use of objective 
imaging. 
 
7.2 
Post protocol completion: Anticoagulation decision algorithm 
 
7.21 
Following the 12 months of protocol completion, a decision regarding 
anticoagulation continuation (off-study) will be clinically determined by the 
medical team caring for the patient.  Although cancer is associated with a high 
risk of recurrent venous thromboembolism, the rate of recurrence differs 
significantly by cancer type, stage of disease, and stage progression over time 
(20).  For the following patient characteristics, we recommend continuing 
anticoagulation: patients with brain, lung, pancreatic, or ovarian cancer; 
myeloproliferative or myelodysplastic disorders; stage IV cancer; cancer stage 
progression; or leg paresis.  Anticoagulation options could include: continue 
apixaban (or other oral novel direct factor inhibitors), LMW heparin (dalteparin 
or enoxaparin), or warfarin.   
 
 
For patients not meeting these specific criteria or if their presenting thrombus 
was limited to the calf (distal to and not including the popliteal vein), it is 
reasonable to discontinue anticoagulation therapy.      
 
7.3  
Breaking Codes in Double-Blinded Studies  
 
 
The treatment code cannot be broken except in the event of an emergency for an 
individual patient. In the event of an emergency, call the ACCRU Registration Office at 
to break the code on Monday through Friday, 8:00 a.m. to 4:30 p.m. 


Amendment 1 
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Central Time. Place a call to the ACCRU Registration Office and leave a message 
informing them of the need to un-blind a patient. Provide your contact information so that 
ACCRU Registration Office personnel can return the call the next business day. If a 
patient has been removed from the study and the clinician believes it is important to 
know what dose the patient was on, they can be unblinded. Before unblinding, all 
protocol data should be collected.  
 
 
8.0 
Dosage Modification Based on Adverse Events  
 
8.1  
Apixaban is cleared through several mechanisms including renal clearance, hepatic 
metabolism, and fecal excretion.  Severe thrombocytopenia, liver and renal failure may 
increase bleeding risk.  Patients with calculated creatinine clearance ≤30 ml/min (using 
the Cockcroft-Gault formula) must hold treatment until renal function improves to 
creatinine clearance >30 ml/min. They may get alternative anticoagulation treatment 
during this time period until renal function improves per the attending physician 
judgment. 
   
For patients receiving either a strong CYP3A4 inducer or a strong CYP3A4 inhibitor 
(Appendix II), the medication should be discontinued or an alternative agent within the 
specific class of drug should be sought in order to participate in this study.  If no good 
alternative agent within that class can be identified and the drug is required, the ACCRU 
Data Manager should be notified and the subject removed from the trial and go to 
observation.   
 
For thrombocytopenia (> 50,000/microliter), no dose adjustment is necessary. For 
thrombocytopenia (< 50,000/microliter), apixaban will be held until platelet count 
recovers.  Once the platelet count improves (≥ 50,000/microliter), the apixaban dose 
should be restarted.      
 
If patients meet criteria for a major bleed, they will have met a major safety endpoint and 
will be removed from the study.  The patient will then be managed, off-study, as 
appropriate per the clinical situation and current guidelines.   
 
If patients meet criteria for a recurrent venous thromboembolic event, they will have met 
a major secondary endpoint and will be removed from the study.  The patient will then be 
managed, off-study, as appropriate per the clinical situation and current guidelines.   
 
If the patient suffers a non-major clinically relevant bleeding event, they will have met a 
major safety endpoint.  Medical management will be provided in accordance with the 
location and severity of the bleeding event.  This may include temporary cessation of 
study medication.  Once the bleeding event has been appropriately managed, they can 
restart study medication, if considered clinically appropriate by the attending physician, 
and can be followed appropriately per protocol.  They do not need to be removed from 
the study for this event.   
     
 
 


Amendment 1 
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ACCRU-SC-1601 
 
8.2 
Patients requiring any invasive procedure requiring temporary anticoagulant 
cessation will be managed as follows:   
 
(1) Date and type of procedure will be recorded on the CRF;  
 
(2)  Apixaban will be discontinued at least 48 hours prior to elective surgery or invasive 
procedures with a moderate or high risk of bleeding, with no drug given on the procedure 
date; For low bleeding risk procedures, apixaban will be discontinued at least 24 hours 
prior to the procedure. 
 
(3) Post procedure, the patient should receive appropriate DVT prophylaxis per 
institutional guidelines.  This could include prophylactic apixaban (open label dose of 2.5 
mg twice daily) dosing for 48 hours; the first prophylactic dose will be given 24 hours 
after the procedure.  Alternatively, low molecular weight heparin or unfractionated 
heparin would be reasonable.    
 
(4) Study drug will be withheld until 48 hours after the procedure and not initiated until 
adequate hemostasis is confirmed.   
 
If apixaban treatment is temporarily held for any situation, the reason will be recorded on 
the CRF and the patient can go back on study for up to day 365 of the treatment schedule.  
  
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Concomitant use of strong CYP3A4 inhibitors or inducers (appendix II) is prohibited.   
 
9.2 
Non-steroid anti-inflammatory drugs (NSAIDs) and antiplatelet agents (aspirin) are 
discouraged but not prohibited. If aspirin use is required, then the dose should be ≤100 
mg daily. The use of these drugs should be recorded on the CRF. 
 
9.3 
Note:  Antiplatelet therapy with a thienopyridine (clopidogrel, prasugrel, or ticagrelor) is 
an exclusion criterion and not allowed while on protocol therapy. 
 
9.4 
Measures necessary for minor and major bleeds should be utilized.  
 
9.5 
Other anticoagulants should not be used concomitantly (aside from those noted in Section 
8.2). 
 
 
 
10.0 
Adverse Event (AE) Reporting and Monitoring 
 
10.1 
Adverse Event Characteristics 
 
 
An Adverse Event [AE] is defined as any new untoward medical occurrence or 
worsening of a preexisting medical condition in a patient or clinical investigation subject 
administered an investigational (medicinal) product and that does not necessarily have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of investigational product, whether or not 
considered related to the investigational product. 
 
 


Amendment 1 
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ACCRU-SC-1601 
 
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
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: 
     
 
10.11 Adverse event monitoring and reporting is a routine part of every clinical trial.  
First, identify and grade the severity of the event using the CTCAE version 4.0.  
Next, determine whether the event is expected or unexpected (see Section 10.2) 
and if the adverse event is related to the medical treatment or procedure (see 
Section 10.3).  With this information, determine whether the event must be 
reported as an expedited report (see Section 10.4).  Important: Expedited adverse 
event reporting requires submission of a Med Watch 3500A report(s). Expedited 
reports are to be completed within the timeframes and via the mechanisms 
specified in Sections 10.4  All AEs reported via expedited mechanisms must also 
be reported via the routine data reporting mechanisms defined by the protocol 
(see Sections 10.5 and 18.0). 
 
10.12 Each CTCAE term in the current version is a unique representation of a specific 
event used for medical documentation and scientific analysis and is a single 
MedDRA Lowest Level Term (LLT).    
 
• 
NOTE:  A severe AE, as defined by the above grading scale, is NOT 
the same as serious AE which is defined in the table in Section 10.4. 
 
10.2  
Expected vs. Unexpected Events  
 
• 
The determination of whether an AE is expected is based on agent-specific 
information provided in Section 15.0 of the protocol. 
 
• 
Unexpected AEs are those not listed in the agent-specific information 
provided in Section 15.0 of the protocol (determined based on Reference 
Safety Information from the current investigator brochure for Apixaban). 
 
NOTE: “Unexpected adverse experiences” means any adverse experience that is neither 
identified in nature, severity, or frequency of risk in the information provided for IRB 
review nor mentioned in the consent form.  
 
10.3 
Assessment of Attribution 
 
When assessing whether an adverse event is related to a medical treatment or 
procedure, the following attribution categories are utilized: 
 
Definite - The adverse event is clearly related to the agent(s). 
Probable - The adverse event is likely related to the agent(s). 
Possible - The adverse event may be related to the agent(s). 
Unlikely - The adverse event is doubtfully related to the agent(s). 
Unrelated - The adverse event is clearly NOT related to the agent(s). 
 
 


Amendment 1 
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ACCRU-SC-1601 
 
Events determined to be possibly, probably or definitely attributed to a 
medical treatment suggest there is evidence to indicate a causal relationship 
between the drug and the adverse event.  
 
10.31 Special Situations for Expedited Reporting  
 
10.311 Persistent or Significant Disabilities/Incapacities 
 
Any AE that results in persistent or significant incapacity or substantial 
disruption of the ability to conduct normal life functions (formerly referred to 
as disabilities), congenital abnormities or birth defects, must be reported 
immediately if they occur at any time following treatment with an agent under 
an IND/IDE since they are considered to be a serious AE and must be reported 
to the sponsor as specified in 21 CFR 312.64(b). 
 
10.312 Death 
 
• 
Any death occurring within 30 days of the last dose, 
regardless of attribution to an agent/intervention under an 
IND/IDE requires expedited reporting within 24-hours. 
 
• 
Any death occurring greater than 30 days with an attribution 
of possible, probable, or definite to an agent/intervention 
under an NCI IND/IDE requires expedited reporting within 
24-hours. 
 
• 
Reportable categories of Death  
 
• 
Death attributable to a CTCAE term. 
 
• 
Death Neonatal:  A disorder characterized by 
cessation of life during the first 28 days of life. 
 
• 
Death NOS:  A cessation of life that cannot be 
attributed to a CTCAE term associated with Grade 5. 
 
• 
Sudden death NOS:  A sudden (defined as instant or 
within one hour of the onset of symptoms) or an 
unobserved cessation of life that cannot be attributed 
to a CTCAE term associated with Grade 5. 
 
• 
Death due to progressive disease should be reported 
as Grade 5 “Neoplasms benign, malignant and 
unspecified (incl cysts and polyps) – Other 
(Progressive Disease)” under the system organ class 
(SOC) of the same name.  Evidence that the death 
was a manifestation of underlying disease (e.g., 
radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a 
disease process) should be submitted. 


Amendment 1 
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ACCRU-SC-1601 
 
  
10.313 Secondary Malignancy 
 
• 
A secondary malignancy is a cancer caused by treatment for a 
previous malignancy (e.g., treatment with investigational 
agent/intervention, radiation or chemotherapy).  A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
 
• 
All secondary malignancies that occur following treatment with an 
agent under an IND/IDE to be reported. Three options are available to 
describe the event: 
 
o Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myeloctyic Leukemia [AML]) 
 
o Myelodysplastic syndrome (MDS) 
 
o Treatment-related secondary malignancy 
 
• 
Any malignancy possibly related to cancer treatment (including 
AML/MDS) should also be reported via the routine reporting 
mechanisms outlined in each protocol. 
 
10.314 Second Malignancy 
 
• 
A second malignancy is one unrelated to the treatment of a prior 
malignancy (and is NOT a metastasis from the initial malignancy).  
Second malignancies require ONLY routine reporting. 
 
10.315  Pregnancy   
  
If, following initiation of the investigational product, it is subsequently 
discovered that a study subject is pregnant or may have been pregnant at 
the time of investigational product exposure, including during at least 5 
half-lives after product administration, the investigational product will be 
permanently discontinued in an appropriate manner (eg, dose tapering if 
necessary for subject safety).  
 
The site investigator must immediately notify ACCRU of this event via 
the Pregnancy Surveillance Form  (found in the forms packet) within 24 
hours and in accordance with SAE reporting procedures in Section 10.4. 
 
Follow-up information regarding the course of the pregnancy, including 
perinatal and neonatal outcome and, where applicable, offspring 
information must be reported on a Pregnancy Surveillance Form. 
 
Any pregnancy that occurs in a female partner of a male study participant 
should be reported to BMS. Information on this pregnancy may also be 
collected on the Pregnancy Surveillance Form. 
 
 
Protocol-required procedures for study discontinuation and follow-up 
must be performed on the subject unless contraindicated by pregnancy 


Amendment 1 
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ACCRU-SC-1601 
 
(eg, x-ray studies). Other appropriate pregnancy follow-up procedures 
should be considered if indicated. 
 
10.316 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. 
10.317 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. 
(NOTE: If liver toxicity becomes clinically apparent, it must be 
evaluated and then reported.) 
 
Adverse drug reactions (related SAEs) should be reported. If hepatic 
failure, clearly occur due to the meta or primary malignancy, it should 
not be considered related, therefore not reportable to BMS. 
 
 
10.318 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. 
 
 
 


Amendment 1 
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ACCRU-SC-1601 
 
 
10.4  
Expedited Reporting Requirements for Studies using Commercial Agent(s) ONLY: 
 
Expedited Reporting Requirements for Adverse Events that Occur in a Non-
IND/IDE trial within 30 Days of the Last Administration of a Commercial Agent 1, 2 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to ACCRU ANY Serious Adverse Events, whether or not they are 
considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
 An adverse event is considered serious if it results in ANY of the following outcomes:   
1) 
Death 
2) 
A life-threatening adverse event  
3) 
An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) 
A congenital anomaly/birth defect.  
6) 
Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to ACCRU within the 
timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
1 Business Day 
24-hour 
1 Business 
Day  
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
1 Business Day  
Expedited AE reporting timelines are defined as: 
o “24-Hour; 1 Business Day” - The AE must initially be reported via MedWatch within 24 hours of learning 
of the AE, followed by a complete expedited report within 1 business day of the initial 24-hour report. 
o “1 Business Day” - A complete expedited report on the AE must be submitted within 1 business day of 
learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 1 business day  for: 
• All Grade 4, and Grade 5 AEs 
Expedited 1 business day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• Grade 3 adverse events 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” above 
applies after this reporting period. 
Effective Date:  May 5, 2011 
 
 
 


Amendment 1 
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ACCRU-SC-1601 
 
Additional Instructions: 
 
1.  An increased incidence of an expected adverse event (AE) is based on the patients treated for 
this study at their site.  A list of known/expected AEs is reported in the package insert or the 
literature, including AEs resulting from a drug overdose. 
 
2.  Follow site-specific reporting guidelines. 
 
3.  Submit form 3500A to the FDA, MedWatch, 
 
   
 
 
4.  Submit copies to the ACCRU SAE Coordinator via fax 
  The ACCRU 
SAE Coordinator will forward   the report to Bristol-Myers Squibb via E-mail within 1 
business day to 
     
 
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. 
 
5.  The ACCRU SAE Coordinator will forward to 
as 
appropriate. The ACCRU IND Coordinator will assist the sponsor-investigator in 
notifying the FDA if required.  
 
 
10.5 
Other Required Reporting 
 
10.51 All adverse events should be graded at each evaluation per the CTCAE v4.0 grading. 
 
10.52 Submit via appropriate Academic and Community Cancer Research United (ACCRU) 
Case Report Forms (i.e., paper or electronic, as applicable) the following AEs 
experienced by a patient and not specified in Section 10.5: 
 
10.521 Grade 2 AEs deemed possibly, probably, or definitely related to the study 
treatment or procedure. 
 
10.522 Grade 3 and 4 AEs regardless of attribution to the study treatment or procedure. 
 
10.523  Grade 5 AEs (Deaths) 
 
10.5231 Any death within 30 days of the patient’s last study  treatment or 
procedure regardless of attribution to the study treatment or procedure. 
 
10.5232 Any death more than 30 days after the patient’s last study treatment or 
procedure that is felt to be at least possibly treatment related must also 


Amendment 1 
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ACCRU-SC-1601 
 
be submitted as a Grade 5 AE, with a CTCAE type and attribution 
assigned. 
 
10.53    Refer to the instructions in the Forms Packet (or electronic data entry screens, as 
applicable) regarding the submission of late occurring AEs following completion of the 
Active Monitoring Phase (i.e., compliance with Test Schedule in Section 4.0). 
 
10.54 Non-Serious Adverse Events (NSAEs) Collecting and Reporting 
 
 
 
The collection of non-serious adverse event (NSAE) information should begin at 
initiation of study drug. Non-serious adverse event information should also be collected 
from the start of a placebo lead-in period or other observational period intended to 
establish a baseline status for the subjects.  
 
 
 
Non-serious AEs should be followed to resolution or stabilization, or reported as SAEs if 
they become serious. Follow-up is also required for non-serious AEs that cause 
interruption or discontinuation of study drug, or those that are present at the end of study 
treatment as appropriate.  
 
 
 
Non-serious Adverse Events will be provided to BMS via the reconciliation report as 
outlined below.  
 
10.55 Reconciliation  
 
 
The Research Coordinating Center 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).  BMS 
GPV&E will e-mail upon request from the Research Coordinating Center, 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 Research Coordinating Center 
determines a case was not transmitted to BMS GPV&E, the case will be sent 
immediately. 
 
11.0 
Treatment Evaluation Using RECIST Guideline – Not applicable  
 
12.0 
Descriptive Factors – Not applicable  
 
13.0 
Treatment/Follow–up Decision at Evaluation of Patient   
 
 
13.1 
A patient is deemed ineligible if after registration, it is determined that at the time of 
registration, the patient did not satisfy each and every eligibility criteria for study entry.  
The patient may continue treatment off-protocol at the discretion of the physician as long 
as there are no safety concerns, and the patient was properly registered. The patient will 
go off study.  
• 
If the patient received treatment, all data up until the point of confirmation of 
ineligibility must be submitted.    
• 
If the patient never received treatment, on-study material must be submitted.   
 
13.2 
It is deemed a major violation, if protocol requirements regarding treatment of the patient 
in cycle 1 of the initial therapy are severely violated that evaluability for primary end 


Amendment 1 
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ACCRU-SC-1601 
 
point is questionable. This determination needs to be made by an investigator blinded to 
treatment allocation.  
 
13.3 
It is deemed a cancel if the patient is removed from the study for any reason before any study 
treatment is given.  On-Study material and the End of Active Treatment/Cancel Notification 
Form must be submitted.  No further data submission is necessary 
 
 
13.4 
If the patient meets criteria for a major bleed, they will have met a major safety endpoint and 
will be removed from the study.  All data up until the point of major bleed should be entered. 
The patient will then be managed as appropriate per the clinical situation and current 
guidelines.   
 
 
13.5 
If the patient meets criteria for a recurrent venous thromboembolic event, they will have met 
a major secondary endpoint and will be removed from the study. All data up until the point of 
a recurrent venous thromboembolic event should be entered. The patient will then be 
managed as appropriate per the clinical situation and current guidelines.   
 
 
13.6 
If the patient suffers a non-major clinically relevant bleeding event, they will have met a 
major safety endpoint.  Medical management will be provided in accordance with the 
location and severity of the bleeding event.  This may include temporary cessation of study 
medication.  Once the bleeding event has been appropriately managed, they will restart study 
medication and will be followed appropriately per protocol.  They will not be removed from 
the study for this event.   
 
13.7  
Disease progression is not a reason for stopping the study medication.  If the patient goes on 
hospice, they may continue the study medication and the protocol procedures.  If it is decided 
that the patient is too ill to stay on the study, then it can be stopped.   
 
14.0 
Body Fluid Biospecimens – Not applicable  
 
15.0 
Drug Information 
 
15.1 
Apixaban (Eliquis®) IND #134645 
 
Review the investigator brochure, available on the ACCRU web site, for the most current 
and complete adverse event information.  
 
 
15.11 Background:    Apixaban (Eliquis) is an oral direct factor Xa inhibitor which 
impairs coagulation by inhibiting the conversion of prothrombin to thrombin.  It 
does not require antithrombin for antithrombotic activity and inhibits both free 
and clot-bound FXa.  Apixaban has an apparent half-life of about 12 hours and 
thus is dosed twice-daily.  Bioavailability is approximately 50% after oral dosing 
with maximum concentrations at 4 hours post ingestion.  The pharmacokinetics 
are linear and plasma protein binding in humans is high at nearly 90% with a 
volume of distribution of approximately 20 liters.  Apixaban is metabolized in 
the liver mainly via the CYP3A4 pathway.  Renal excretion accounts for about 
27% of total clearance.  Approximately 25% of the drug is eliminated in the 
feces. This drug is not dialyzable due to its high plasma protein binding.  
Apixaban is currently FDA approved for prevention and treatment of venous 
thromboembolism and stroke prevention in the setting of non-valvular atrial 
fibrillation. 


Amendment 1 
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ACCRU-SC-1601 
 
 
 
15.12 Formulation: Apixaban (Eliquis®) tablets are available for oral administration in 
strengths of 2.5 mg and 5 mg of apixaban. Both tablets have the appearance of 
Reddish brown, plain, oval shaped, shallow biconvex film coated tablets. 
 
 
15.13 Preparation and storage: Store at room temperature 2°C to 30°C (36°F-86°F).  
Please see current investigator brochure.  
 
 
15.14 Administration:  Apixaban will be provided in bottles containing 200 tablets of 
either 2.5 mg or 5 mg.   
 
 
 
Administer without regard to meals.  If patient is unable to swallow whole tablets 
whole, 2.5 or 5 mg tablets may be crushed and suspended in water, 5% dextrose 
in water (D5W), apple juice, or apple puree and promptly administered orally.  
Crushed apixaban tablets are stable in water, D5W, apple juice and apple puree 
for up to 4 hours. Tablets may also be crushed and suspended in 60 mL of 
dextrose 5% in water followed by immediate delivery through a nasogastric tube.  
 
 
15.15 Appearance:   
 
 
Study drug allocation will be blinded and could be to either apixaban 2.5 mg 
dose or 5 mg dose.  Both doses will be blinded by the company such that neither 
the investigator nor the patient will know which tablet strength they are using. 
   
 
15.16 Pharmacokinetic information: 
a)  Absorption – Time to peak after oral administration is 3 to 4 hours; 
bioavailability is approximately 50% for doses up to 10 mg. 
b)  Distribution – Plasma protein binding in humans is approximately 87%. The 
steady-state volume of distribution is approximately 21 L.  
c)  Metabolism – Hepatic predominantly via CYP3A4 and to a lesser extent via 
CYP1A2, 2C8, 2C9, 2C19, and 2J2; substrate of P-glycoprotein (P-gp) and 
breast cancer resistant protein (BCRP) 
d) Excretion – Urine (27% as parent drug); feces 
e)  Half-life Elimination – approximately 12 hours 
 
 
15.17 Potential drug interactions:  Apixaban is a substrate of both CYP3A4 and P-gp. 
 
Inhibitors of CYP3A4 and P-gp increase exposure to apixaban and increase the 
 
risk of bleeding. Inducers of CYP3A4 and P-gp decrease exposure to apixaban 
 
and increase the risk of stroke and other thromboembolic events.  
 
 
Avoid concomitant use with dual strong CYP3A4 and P-glycoprotein inhibitors 
 
(eg, clarithromycin, ketoconazole, itraconazole, ritonavir). 
 
 
Anticoagulants: Apixaban may enhance the anticoagulant effect of other
 
Anticoagulants.  Risk X: Avoid combination 
 
 
 
Combination with fibrinolytics increases the risk of bleeding.  
Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, 
 
etc.) may enhance the adverse/toxic effect of Apixaban. Specifically, the risk 
 
for bleeding may be increased. Risk C: Monitor therapy  
 
 
CYP3A4 Inducers (Moderate): May decrease the serum concentration of 
 
CYP3A4 Substrates. Risk C: Monitor therapy 
 
 
CYP3A4 Inducers (Strong): May decrease the serum concentration of Apixaban. 
 
Risk X: Avoid combination 
 
 
CYP3A4 Inhibitors (Moderate): May decrease the metabolism of CYP3A4 


Amendment 1 
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ACCRU-SC-1601 
 
 
Substrates. Risk C: Monitor therapy 
 
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Apixaban. 
Management: Apixaban U.S. prescribing information states dose reduction 
criteria that may be applied under some circumstances.  See full interaction 
monograph for details. Risk X: Avoid combination 
 
 
Exceptions: Clarithromycin; Cobicistat; Darunavir; Itraconazole; Ketoconazole 
 
 
(Systemic); Lopinavir; Ombitasvir, Paritaprevir, and Ritonavir; Ritonavir; 
 
 
Saquinavir; Telaprevir.  Risk C: Monitor therapy.  
 
 
Inhibitors of CYP3A4 (Strong) and P-glycoprotein: May increase the serum 
 
 
 concentration of Apixaban. Management: US labeling recommends a 50% 
 
 
 apixaban dose reduction in patients who would otherwise receive 5 or 10 mg 
 
 
 twice daily, and avoiding in patients who would otherwise receive 2.5 mg twice 
 
 
 daily. Canadian labeling lists any combined use as contraindicated. Risk D: 
 
 
 Consider therapy modification. 
 
 
 
 
 
Grapefruit juice may increase levels/effects of apixaban. Management: Advise 
 
patients who consume grapefruit juice during therapy to use caution; monitor for 
 
increased effects (eg, bleeding).  
 
 
  
15.18 Known potential toxicities:   
 
 
Consult the current investigator brochure for the most current and complete 
information. 
 
 
Adverse effects by frequency: 
 
 
>10%:  
 
 
Hematologic & oncologic: Hemorrhage (1% to 12%; major: ≤3%;  
 
clinically relevant non-major bleeding: 2% to 4%) 
 
 
 
 
1% to 10%: 
 
 
 
Endocrine & metabolic: Increased gamma-glutamyl transferase (≤1%) 
 
Gastrointestinal: Nausea (3%) 
 
Hematologic & oncologic: Anemia (3%), bruise (1% to 2%), 
 
Post-procedural hemorrhage (≤1%) 
 
 
 
Hepatic: Increased serum transaminases (≤1%) 
 
 
 
<1% (Limited to important or life-threatening):  
 
 
Anaphylaxis, gastrointestinal hemorrhage, hematuria, hemophthalmos, 
hypersensitivity, hypotension, incision site hemorrhage, increased serum alkaline 
phosphatase, increased serum AST, increased serum bilirubin, intracranial 
hemorrhage, muscle hemorrhage, perioperative blood loss, postoperative 
hematoma (incision site), rectal hemorrhage, syncope, thrombocytopenia, wound 
secretion 
 
 
15.19a  Drug procurement:  Bristol Myers-Squibb will supply apixaban labeled for 
investigational use to Biologics, Inc.   


Amendment 1 
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ACCRU-SC-1601 
 
 
Each participating ACCRU treating location will order a starter supply of blinded 
apixaban 5mg/apixaban 2.5mg from Biologics. Fax the Drug Order Request 
Form (found in the forms packet) to the following:  
 
 
 
ACCRU Registration Office personnel will monitor the supply of blinded 
apixaban at each participating location and will arrange for Biologics to send 
additional supplies, as needed. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place 
at each institution. 
 
 
15.19b Nursing guidelines   
 
• 
Warn patient to avoid taking medication with any other agents (i.e., aspirin, 
NSAIDS, etc.). 
• 
Warn patients of risk of bleeding, including serious life-threatening internal 
bleeding. 
• 
Patients may bruise easily. Instruct patients to report excessive bruising to 
study team. 
• 
Rarely patients may have nausea;, treat symptomatically and monitor for 
effectiveness. 
• 
Patients should be instructed to let all providers know they are taking 
medication especially prior to any surgical/invasive procedure. 
• 
Patients should be instructed to avoid agents that utilize the CYP3A4 
pathway. Instruct patients to contact the study team prior to starting any new 
medications. 
• 
Rarely LFTs may increase; monitor LFTs per protocol. 
  
 
16.0  
Statistical Considerations and Methodology  
  
16.1 
Sample Size Determination 
 
The primary objective of this study is to determine whether apixaban 2.5 mg twice daily 
has less bleeding (major bleeding plus clinically relevant nonmajor bleeding) compared 
to apixaban 5 mg twice daily for secondary VTE prevention in patients with active 
cancer, previously confirmed deep-vein thrombosis (DVT) or pulmonary embolism (PE) 
for which they have completed at least 6 months (but no more than 12 months) of 
anticoagulant therapy.  Important assumptions include both clinical and trial observation 
that bleeding rates in cancer patients with VTE are higher than non-cancer patients.  As 
such, a recent meta-analysis of cancer patients treated with direct factor inhibitors 
showed that rates of major bleeding were 3.2% and clinically relevant non-major 
bleeding 14.5% (19).  This would equate to rates of 17.7% for these combined outcomes.   
 


Amendment 1 
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ACCRU-SC-1601 
 
The trial is designed as a two-arm, double-blind, randomized study.  Patients will be 
randomized at a 1:1 ratio to receive either 5 mg or 2.5 mg of apixaban twice daily.  
Assuming the combined bleeding event rate is 9% in the 2.5 mg arm, and 18% in the 5 
mg arm, a sample size of 352 (176 per arm) will give us approximately 70% power to 
detect a difference between the two arms (using a two-sample comparison of proportions 
with a two-sided alternative at a 5% significance level). The sample size is inflated by 5% 
to a total of 370 (185) to account for ineligibility and cancellation.  We anticipate 
accruing 15 patients per month to this trial.  Based on this accrual rate, we anticipate the 
trial will complete accrual in 24 months.  With the last patient accrued followed for 12 
months , the primary analysis will be conducted approximately 36 months after the trial 
opening. The sample was calculated using EAST 6.3 (Cytel Inc.). 
 
16.2 
Primary Hypothesis:  
 
We hypothesize that apixaban 2.5 mg twice daily is associated with a significantly lower 
combined rate of major bleed plus clinically relevant nonmajor bleed compared to 
apixaban 5 mg twice daily for the secondary prevention of VTE in patients with active 
cancer and confirmed deep-vein thrombosis (DVT) or pulmonary embolism (PE) who 
have completed at least 6 months (but no more than 12 months) of anticoagulant therapy. 
 
16.21 Primary Safety Analysis:  
 
All patients who received at least one dose of either apixaban 2.5 mg or apixaban 
5 mg will be included in the primary analysis. Patients will be analyzed 
according to the drug they received because this is a safety analysis rather than an 
efficacy analysis. The analysis of major bleeding plus clinically relevant 
nonmajor bleeding events will primarily focus on those events which occurred 
during treatment or within 7 days of treatment discontinuation. Major bleeding 
events observed later will be described separately.   
 
It should be noted that this study is powered for our primary analysis, in which 
the proportion of patients experiencing at least one bleeding event within 12 
months of beginning treatment will be compared across the two study arms using 
a two-sample comparison of proportions with a one-sided alternative at a 
significance level of 5% (i.e. a “Z” test).     
 
Though not part of the primary analysis, a number of additional analyses of the 
primary endpoint will also be performed to further explore the data.  These 
should be viewed as additional secondary analyses.  In particular, frequency of 
major bleeding and clinically relevant non-major bleeding will be tabulated by 
treatment arm.  Incidence of major bleeding and clinically relevant non-major 
bleeding will be estimated using the cumulative incidence function with death 
without major bleeding or clinically relevant non-major bleeding and with 
adverse events that results in termination of treatment (including vascular events) 
as competing risks.  The time to event is defined as the time from randomization 
to the first occurrence of a major bleeding, a clinically relevant non-major 
bleeding, death without major bleeding or clinically relevant non-major bleeding, 
or an adverse events that results in termination of treatment (including vascular 
events).  Patients who were lost to follow-up, who withdrew informed consent 
before the end of the predefined study duration will be censored at the last day 
the patient had a complete assessment for study outcomes within the intended 


Amendment 1 
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ACCRU-SC-1601 
 
study period. The incidence curves of major bleeding and clinically relevant non-
major bleeding will be plottted.  The incidence of major bleeding and clinically 
relevant non-major bleeding will be summarized as a combined endpoint and 
separate endpoints by treatment arm.  The difference in the incidences of the 
combined endpoint at 6 months and at 12 months between treatment arms will be 
estimated and tested using a normal approximation of the binomial distribution. 
All tests will be conducted at the one-sided 0.05 significance level. 
 
The incidences of death due to cancer or other causes (without major bleeding or 
clinically relevant non-major bleeding) and adverse events that result in 
termination of treatment will be estimated and compared using the same 
approach.   
 
A sensitivity analysis for these endpoints will be conducted using a stratified (by 
stratification factors listed in Section 5.0) Cox model adjusting for baseline 
covariates including location of DVT, renal clearance, age, sex, mobility at 
randomization, pulmonary disease, and cardiac disease. 
   
16.22 Secondary  Safety Analysis: 
 
A secondary safety analysis of the primary safety endpoint will be performed on 
an intent-to-treat basis using the same approach described in Section 16.21.  In 
addition, we will compare proportion of patients who experience at least one 
bleeding event (i.e. the primary endpoint) within 6 months of beginning 
treatment across the two study arms.  As with the primary analysis, this will be 
done using a two-sample comparison of proportions with a one-sided alternative 
at a significance level of 5%. 
 
16.23 Secondary Efficacy Analysis: 
   
For the secondary efficacy analysis, the time to the first event of the composite 
DVT/PE outcome will be analyzed using the same method described in Section 
16.21.  For this outcome, death without DVT/PE and adverse events leading to 
termination of treatment will be treated as the competing risks. 
 
16.3 
Handling of Missing Data: 
 
Monitoring and auditing procedures should be followed, in order to comply with Good 
Clinical Practice (GCP) guidelines. Each center will be audited at regular intervals to 
ensure compliance with the protocol, GCP and legal aspects. This will include on-site 
checking of the CRF for completeness and clarity, cross-checking with source 
documents, and clarification of administrative matters. 
 
16.4 
Interim Analysis and Study Monitoring:  
 
No formal interim analysis is planned. Risk-benefit will be evaluated by the Mayo Clinic 
Data Safety and Monitoring Board (DSMB), which will give regular recommendation to 
the executive committee. Early termination of accrual will be considered if there is 
evidence of   a significant difference in major bleeding rates between the comparators.  
Access to interim tabular risk benefit data will be restricted. 
 


Amendment 1 
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ACCRU-SC-1601 
 
16.5 
Adverse Event Stopping Rule:  
 
The stopping rule specified below is based on the knowledge available at study 
development. We do note that the Adverse Event Stopping Rule may be adjusted in the 
event of either (1) the study re-opening to accrual or (2) at any time during the conduct of 
the trial and in consideration of newly acquired information regarding the adverse event 
profile of the treatment(s) under investigation. The study team may choose to suspend 
accrual because of unexpected adverse event profiles that have not crossed the specified 
rule below. 
 
Accrual will be temporarily suspended to this study if at any time we observe events that 
the study team considers to be at least possibly related to study treatment (i.e., an adverse 
event with attribute specified as “possible,” “probable,” or “definite”) that satisfy the 
following: 
 
 • If 5 or more patients in the first 20 treated patients of either of the study arms (or 
20% of all patients after 20 are accrued) experience a grade 4 or higher non-
hematologic adverse event. 
 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or 
“unlikely to be related” to verify their attribution and to monitor the emergence 
of a previously unrecognized treatment-related adverse event. 
 
17.0  
Pathology Considerations/Tissue Biospecimens – Not applicable  
 
 
 


Amendment 1 
32  
ACCRU-SC-1601 
 
18.0 
Records and Data Collection Procedures 
 
18.1 Submission Timetable 
 
NOTE: Access the RAVE system through the iMedidata portal at 
All data must be entered by Remote Date Entry (RDE) and 
completed by qualified and authorized personnel. All data on the CRF must reflect the 
corresponding source document. Please refer to the ACCRU website for instructions 
 
 
 
 Initial Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
Institutional Contacts 
 
≤2 weeks after registration 
On Study  
Laboratory Tests and Results: Baseline 
Patient Status: Baseline 
Concomitant Medications  
Off Treatment  
Submit ≤1 week  after registration if withdrawal/refusal occurs 
prior to beginning protocol therapy 
 
 
Test Schedule Material(s) 
CRF 
Active Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
At each monthly evaluation 
during treatment 
At end of treatment 
  
Treatment (Intervention) 
X 
X 
Treatment (Intervention): Dose Omissions 
X 
X 
Recurrent Thromboembolism 
X 
X 
Adverse Events: Solicited 
X 
X 
Adverse Events: Other 
X 
X 
Non-CTCAE Bleeding Grading  
X 
X 
Concomitant Medications 
X 
X  
Patient Status: Treatment 
X 
 
Off Treatment  
 
X 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
Deviation 
At each occurrence 
(see Section 10.0) 
 
  
    
 
 


Amendment 1 
33  
ACCRU-SC-1601 
 
19.0  
Budget 
 
19.1 
Each site should review the test schedule (Section 4.0), taking into account local and 
regional coverage policies, to determine which items are standard of care and which are 
research at their site.  Refer to the payment synopsis for funding provided per accrual for 
covering study costs, as well as any additional invoiceables that may be allowed. 
 
 
19.2 
Tests to be research funded:  none. 
 
19.3 
Other budget concerns:  The study drug, apixaban (2.5 mg or 5 mg), will be supplied free 
of charge by Bristol Myers-Squibb.   
 
20.0 
References 
 
1. Heit JA, Mohr DN, Silverstein MD, Petterson TM, O’Fallon WM, Melton LJ III. Predictors of 
recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. 
Arch Intern Med. 2000;160(6):761-768. 
2. Hutten BA, Prins MH, Gent M, Ginsberg J, Tijssen JG, B¨ uller HR. Incidence of recurrent 
thromboembolic and bleeding complications among patients with venous thromboembolism in 
relation to both malignancy and achieved international normalized ratio: a retrospective analysis. 
J Clin Oncol. 2000; 18(17):3078-3083. 
3. Hansson PO, S¨orbo J, Eriksson H. Recurrent venous thromboembolism after deep vein 
thrombosis: incidence and risk factors. Arch Intern Med. 2000;160(6):769-774. 
4. Douketis JD, Foster GA, Crowther MA, Prins MH, Ginsberg JS. Clinical risk factors and timing 
of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. Arch 
Intern Med. 2000;160(22):3431-3436. 
5. Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism and bleeding 
complications during anticoagulant treatment in patients with cancer and venous thrombosis.  
Blood. 2002;100(10):3484-3488. 
6. Cushman M, Tsai AW, White RH, et al. Deep vein thrombosis and pulmonary embolism in two 
cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med. 2004; 
117(1):19-25. 
7. Descourt R, Le Gal G, Couturaud F, et al. Recurrent venous thromboembolism under 
anticoagulant therapy: a high risk in adenocarcinoma? Thromb Haemost. 2006;95(5): 912-913. 
8. Heit JA, Lahr BD, Petterson TM, Bailey KR, Ashrani AA, Melton LJ III. Heparin and warfarin 
anticoagulation intensity as predictors of recurrence after deep vein thrombosis or pulmonary 
embolism: a population-based cohort study. Blood. 2011;118(18):4992-4999. 
9. Trujillo-Santos J, Ruiz-Gamietea A, Luque JM, et al; RIETE Investigators. Predicting recurrences 
or major bleeding in women with cancer and venous thromboembolism. Findings from the 
RIETE Registry. Thromb Res. 2009;123(Suppl2): S10-S15. 
10. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, 
Morris TA, Sood N, Stevens SM, Vintch JR, Wells P, Woller SC, Moores L.  Antithrombotic 
Therapy for VTE Disease: CHEST Guideline and Expert Panel Report.  Chest. 2016;149:315-52. 
11. Palareti G, Legnani C, Lee A, et al. A comparison of the safety and efficacy of oral 
anticoagulation for the treatment of venous thromboembolic disease in patients with or without 
malignancy. Thromb Haemost. 2000;84(5):805-810. 
12. Elting LS, Escalante CP, Cooksley C, et al. Outcomes and cost of deep venous thrombosis among 
patients with cancer. Arch Intern Med. 2004;164(15):1653-1661. 
13. Gross CP, Galusha DH, Krumholz HM. The impact of venous thromboembolism on risk of death 
or hemorrhage in older cancer patients. J Gen Intern Med. 2007;22(3):321-326. 


Amendment 1 
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ACCRU-SC-1601 
 
14. Ru´ız-Gim´enez N, Su´arez C, Gonz´ alez R, et al; RIETE Investigators. Predictive variables for 
major bleeding events in patients presenting with documented acute venous thromboembolism. 
Findings from the RIETE Registry. Throm Haemost. 2008;100(1):26-31. 
15. Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, Wong T, Cook R, Solymoss S, Poon 
MC, Raskob G; LITE Trial Investigators.  Long-term low-molecular-weight heparin versus usual 
care in proximal-vein thrombosis patients with cancer.  Am J Med. 2006;119:1062-72. 
16. Napolitano M, Saccullo G, Malato A, Sprini D, Ageno W, Imberti D, Mascheroni D, Bucherini E, 
Gallucci P, D'Alessio A, Prantera T, Spadaro P, Rotondo S, Di Micco P, Oriana V, Urbano O, 
Recchia F, Ghirarduzzi A, Lo Coco L, Mancuso S, Casuccio A, Rini GB, Siragusa S.Optimal 
duration of low molecular weight heparin for the treatment of cancer-related deep vein 
thrombosis: the Cancer-DACUS Study. J Clin Oncol. 2014 Nov 10;32(32):3607-12.  
17. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, 
Thompson J, Raskob GE, Weitz JI; the AMPLIFY Investigators. Oral Apixaban for the 
Treatment of Acute Venous Thromboembolism.  N Engl J Med. 2013 Aug 29;369(9):799-808. 
18. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz 
JI; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism.  
N Engl J Med. 2013 Feb 21;368(8):699-708.  
19. Vedovati MC, Germini F, Agnelli G, et al. Direct oral anticoagulants in patients with VTE and 
cancer: A systematic review and meta-analysis. Chest 2015; 147:475-483. 
20. Chee CE, Ashrani AA2, Marks RS3, Petterson TM4, Bailey KR4, Melton LJ 3rd5, Heit JA6. 
Predictors of venous thromboembolism recurrence and bleeding among active cancer patients: a 
population-based cohort study.  Blood. 2014; 123:3972-8.  
21. Schulman S, and Kearon C. Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3:692-694. 
 
 
 


Amendment 1 
 
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Page 1 of 8 
 
Appendix I 
Model Consent Form  
ACCRU Informed Consent Template for Cancer Treatment Trials 
(English Language) 
 
 
*NOTES FOR LOCAL INVESTIGATORS: [NOTE: Retain this section and asterisk item below 
for ACCRU model consents] 
• 
The goal of the informed consent process is to provide people with sufficient information for 
making informed choices.   The informed consent form provides a summary of the clinical study 
and the individual's rights as a research participant.  It serves as a starting point for the necessary 
exchange of information between the investigator and potential research participant.  This 
template for the informed consent form is only one part of the larger process of informed consent. 
For more information about informed consent, review the "Recommendations for the 
Development of Informed Consent Documents for Cancer Clinical Trials" prepared by the 
Comprehensive Working Group on Informed Consent in Cancer Clinical Trials for the National 
Cancer Institute.  The Web site address for this document is 
 
• 
A blank line, __________, indicates that the local investigator should provide the appropriate 
information before the document is reviewed with the prospective research participant.  
• 
Suggestion for Local Investigators:  An NCI pamphlet explaining clinical trials is available for 
your patients.  The pamphlet is entitled: "If You Have Cancer…What You Should Know about 
Clinical Trials".  This pamphlet may be ordered on the NCI Web site at 
 to request a 
free copy.  
• 
Optional feature for Local Investigators: Reference and attach drug sheets, pharmaceutical 
information for the public, or other material on risks.  Check with your local IRB regarding 
review of additional materials. 
 
*These notes for {authors and} investigators are instructional and should not be included in the informed 
consent form given to the prospective research participant.  
 
 
 
 


Amendment 1 
 
ACCRU-SC-1601 
Page 2 of 8 
 
ACCRU-SC-1601, A Phase III, Randomized, Controlled, Double-Blind Study  
Evaluating the Safety of Two Doses of Apixaban for Secondary Prevention of Cancer 
Related Venous Thrombosis in Subjects Who Have Completed at Least  
Six months of Anticoagulation Therapy 
 
This is an important form.  Please read it carefully.  It tells you what you need to know about this research 
study.  If you agree to take part in this study, you need to sign this form.  Your signature means that you 
have been told about the study and what the risks are.  Your signature on this form also means that you 
want to take part in this study. 
 
This is a clinical trial, a type of research study.  Your study doctor will explain the clinical trial to you.   
Clinical trials include only people who choose to take part. Please take your time to make your decision 
about taking part.  You may discuss your decision with your friends and family.  You can also discuss it 
with your health care team.  If you have any questions, you can ask your study doctor for more 
explanation.  
 
You are being asked to take part in this research study because you have received treatment for 
cancer and will also be receiving treatment for a blood clot, deep vein thrombosis or pulmonary 
embolism.   
 
Why is this research study being done? 
 
It is known that having cancer and receiving treatment for cancer can cause side effects, such as blood 
clots.  The purpose of this research study is to compare the effects, good and/or bad, of two different 
doses of apixaban (Eliquis®) 2.5 mg or 5 mg on you and your blood clot, to find out which is better in 
preventing and treating blood clots.  In this study, you will get either apixaban 2.5 mg or 5 mg twice 
daily.  You will not get both. 
 
How many people will take part in the research study? 
 
About 370 people will take part in this study.   
 
What will happen if I take part in this research study? 
 
Before you begin the study treatment 
 
You will need to have the following exams, tests or procedures to find out if you can be in the study.  
These exams, tests or procedures are part of regular cancer care and may be done even if you do not join 
the study.  If you have had some of them recently, they may not need to be repeated.  This will be up to 
your study doctor. 
 
• 
Medical history and physical exam (including weight and height, and a rating of how well you 
perform activities of daily living) 
• 
Routine blood tests  
• 
Pregnancy test if you are a woman of childbearing potential 
• 
Current list of medications 
 
 
 


Amendment 1 
 
ACCRU-SC-1601 
Page 3 of 8 
During the study  
 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, then 
you will need the following tests and procedures.  They are part of regular care for cancer or for blood 
clots.  
 
• 
Medical history and physical exam (including weight and height, and a rating of how well you 
perform activities of daily living) 
• 
Evaluation of symptoms/side effects 
• 
Current list of medications 
 
During the study, you will be "randomized" into one of the study groups described below. Randomization 
means that you are put into a group by chance, as in the flip of a coin. A computer program will place you 
in one of the study groups. Neither you nor your doctor can choose the group you will be in. Neither you 
nor your doctor will know which dose of apixaban you will receive.  You have an equal chance of being 
placed in either group.   
 
If you are in group 1, you will receive the study drug apixaban.  This is a pill and you will take 2.5 
mg by mouth twice a day for 12 months. Every 30 days you will visit your study doctor for a short 
follow-up visit that will include the following: 
• 
Height;  
• 
Weight;  
• 
A check to see if you are having any side effects from the study medication; 
• 
A review of all medications you are currently taking in addition to the study medication.  
• 
Bleeding assessment: You will be asked questions about any bleeding you have 
experienced.  
 
If you are unable to visit your study doctor, a member of the study team will contact you by phone 
every 30 days to ask about the items listed above.    
 
If you are in group 2, you will receive the study drug apixaban.  This is a pill and you will take 5 mg 
by mouth twice a day for 12 months.  Every 30 days you will visit your study doctor for a short 
follow-up visit that will include the following: 
• 
Height;  
• 
Weight;  
• 
A check to see if you are having any side effects from the study medication; 
• 
A review of all medications you are currently taking in addition to the study medication. 
• 
Bleeding assessment: You will be asked questions about any bleeding you have 
experienced.  
 
If you are unable to visit your study doctor, a member of the study team will contact you by phone 
every 30 days to ask about the items listed above.  
 
We want to find out if the apixaban 2.5 mg will help to prevent blood clots and reduce the risk of bleeding 
better than the apixaban 5 mg. You will not know which study drug you will be receiving.   
 
When I am finished taking apixaban for 12 months, what will happen?  
 
At the end of the study treatment period (12 months or 365 days), you can be seen by your doctor to 
determine whether you should continue to take blood thinners or stop taking blood thinners.  If it is 


Amendment 1 
 
ACCRU-SC-1601 
Page 4 of 8 
decided that you should continue to take blood thinners, a prescription for the treatment will need to be 
given to you by your doctor.   
 
The End of Treatment follow-up visit will include the following (NOTE: if you are unable to visit your 
study doctor, a member of the study team will contact you by phone): 
• 
A check to see if you are having any side effects from the study medication; 
• 
A review of all medications you are currently taking in addition to the study medication.  
• 
Bleeding assessment. 
 
If you cannot complete the treatment because you develop a blood clot or start bleeding, the following 
tests may be done.  This will be up to your doctor.  They are part of your regular care for cancer or for 
blood clots.  
 
• 
Routine blood tests  
• 
Ultrasound or CT scan   
 
How long will I be in the research study? 
 
You will be asked to take the apixaban for a total of 12 months.   
 
Can I stop being in the research study? 
 
Yes.  You can decide to stop at any time.  Tell the study doctor if you are thinking about stopping or 
decide to stop.  He or she will tell you how to stop the study drug safely.  
 
It is important to tell the study doctor if you are thinking about stopping so any risks from the apixaban 
can be evaluated by your doctor.  Another reason to tell your doctor that you are thinking about stopping 
is to discuss what follow-up care and testing could be most helpful for you. 
 
The study doctor may stop you from taking part in this study at any time if he/she believes it is in your 
best interest; if you do not follow the study rules; or if the study is stopped. 
 
What side effects or risks can I expect from being in the research study? 
 
You may have side effects while on the study.  You will be watched carefully for any side effects.  
However, doctors may not know all the side effects that may happen.  Side effects may be mild to very 
serious.  Your health care team may give you medicines to help lessen side effects.  Many side effects go 
away soon after you stop taking apixaban.  In some cases, side effects can be serious, long lasting, or may 
never go away.  There also is a risk of death.  
 
You should talk to your study team about any side effects that you have while taking part in the study.    
 
Risks and side effects related to apixaban include those which are: 
 
Likely (>1%) 
• 
Minor bleeding from the nose 
• 
Bruising 
• 
Blood in the urine 
• 
Heavy menstrual bleeding 
• 
Collection of blood under the skin 


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ACCRU-SC-1601 
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• 
Coughing up blood 
• 
Rectal bleeding 
• 
Gum bleeding 
 
Rare but serious (≥ 0.1% to < 1%) 
• 
Serious bleeding from the stomach or intestines  
• 
Throwing up blood 
• 
Serious bleeding into the eye 
• 
Serious bleeding around the heart 
• 
Serious bleeding into the muscles 
• 
Allergic reactions to drug including low platelet count or liver damage 
• 
Bleeding that causes death  
• 
Abnormal or longer than normal vaginal bleeding 
• 
Serious blood loss causing damage to internal organs 
 
Reproductive risks:  You should not become pregnant or father a baby while on this study because the 
drugs in this study can affect an unborn baby.  Women should not breastfeed a baby while on this study.  
It is important you understand that you need to use effective birth control while on this study.  Check with 
your health care provider about what kind of birth control methods to use and how long to use them.  
Some methods might not be approved for use in this study. 
 
For more information about risks and side effects, ask your study doctor. 
 
Are there benefits to taking part in the research study? 
 
Taking part in this study may or may not make your health better.  While doctors hope the study drug will 
be more useful in preventing and treating blood clots in cancer patients, compared to the usual treatment, 
there is no proof of this yet.  We do know that the information from this study will help doctors learn 
more about the study drug to try to prevent and/or treat blood clots.  This information could help future 
patients. 
 
What other choices do I have if I do not take part in this research study? 
 
You do not have to be in this study to receive treatment for your cancer related blood clot. 
 
Your other choices may include: 
• 
Getting treatment or care for your cancer-related blood clot without being in a study 
• 
Taking part in another study 
• 
Getting no treatment 
  
Because blood clots are serious and potentially dangerous, it is important to discuss all treatment options 
with your doctor.  Talk to your doctor about your choices before you decide if you will take part in this 
study. 
 
Will my medical information be kept private? 
 
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Your personal information may be given out if 
required by law.  If information from this study is published or presented at scientific meetings, your 
name and other personal information will not be used.  


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Organizations that may look at and/or copy your medical records for research, quality assurance, and data 
analysis include: 
• 
Government agencies, like the Food and Drug Administration (FDA), involved in keeping 
research safe for people 
• 
Academic and Community Cancer Research United (ACCRU) 
• 
Mayo Clinic Rochester   
• 
Bristol Myers-Squibb 
• 
Institutional Review Boards (IRB) or Ethics Committees (committees that have reviewed this 
study to help ensure the study is conducted in a safe and ethical manner, and that the rights of 
study participants are respected). 
 
A description of this clinical trial will be available on 
as required by U.S. 
Law. This web site will not include information that can identify you. At most, the web site will include a 
summary of study results.  You can search this web site at any time. 
 
Tests done at hospitals or clinics other than the study clinic 
 
If you have blood tests or other medical tests such as scans or x-rays at a clinic or hospital other than to 
the study clinic [insert name of institution], your study doctor may need to review results of these tests as 
they relate to this study.  
 
 
Please read the following statements and mark your choice: 
 
I permit  
 
 
 [investigator’s name(s)] to obtain medical information from my primary 
care giver  
 
 
 
[primary caregiver’s name(s)]as it relates to this study. This may 
include information regarding any blood tests, x-rays or scans: 
 
 Yes 
 
 No  
Please initial here: 
 
 
Date: 
 
 
 
What are the costs of taking part in this research study? 
 
You and/or your health plan/ insurance company will need to pay for some or all of the costs of treating 
your cancer in this study.  Some health plans may not pay these costs for people taking part in studies.  
Check with your health plan or insurance company to find out what they will pay for.  Taking part in this 
study may or may not cost your insurance company more than the cost of getting regular cancer 
treatment.  
 
The study agent, apixaban, will be provided free of charge while you are taking part in this study.   
 
You will not be paid for taking part in this study. 
 
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute’s Web site at 
.    You can print 
a copy of the “Clinical Trials and Insurance Coverage” information from this Web site. 
 
Another way to get the information is to call 
and ask them to send 
you a free copy. 


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What happens if I am injured because I took part in this research study? 
 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], if you feel 
that you have been injured because of taking part in this study.  You can tell the doctor in person or call 
him/her at __________________ [telephone number]. 
 
You will get medical treatment if you are injured as a result of taking part in this study.  You and/or your 
health plan will be charged for this treatment.   The study will not pay for medical treatment.   
 
What are my rights if I take part in this research study? 
 
Taking part in this study is your choice.  You may choose either to take part or not to take part in the 
study.  If you decide to take part in this study, you may leave the study at any time.   No matter what 
decision you make, there will be no penalty to you and you will not lose any of your regular benefits.  
Leaving the study will not affect your medical care.  You can still get your medical care from our 
institution.    
 
We will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study. 
 
In the case of injury resulting from this study, you do not lose any of your legal rights to seek payment by 
signing this form.   
 
Who can answer my questions about the research study? 
 
You can talk to your study doctor about any questions or concerns you have about this study.  Contact 
your study doctor __________________ [name(s)] at __________________ [telephone number]. 
 
For questions about your rights while taking part in this study, call the ________________________ 
[name of center] Institutional Review Board (a group of people who review the research to protect your 
rights) at __________________ (telephone number).  [Note to Local Investigator: Contact information 
for patient representatives or other individuals in a local institution who are not on the IRB or research 
team but take calls regarding clinical trial questions can be listed here.]    
 
Where can I get more information? 
 
You may call the National Cancer Institute's Cancer Information Service at:  
 
  
 
You may also visit the NCI Web site at 
 
 
• 
For NCI’s clinical trials information, go to: 
 
 
• 
For NCI’s general information about cancer, go to 
 
 
You will get a copy of this form.  If you want more information about this study, ask your study doctor. 
 


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ACCRU-SC-1601 
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Signature 
 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.  I have read it 
or it has been read to me.  I understand the information and have had my questions answered.  I agree to 
take part in this study. 
 
 
Printed Participant Name: __________________________________________ 
 
 
Participant Signature: ______________________________________________ 
 
 
Date: _____________________________________ 
 
 
Printed name of person obtaining informed consent:  
 
__________________________________________ 
 
 
Signature of person obtaining informed consent: 
 
___________________________________________ 
 
 
Date _____________________________________ 
 
 
 
 
 
 
 
 
 
 
 
This model informed consent form has been reviewed by the ACCRU and is the official consent 
document for this study.  Local IRB changes to this document are allowed.  Sections “What are the risks 
of the research study” or “What other choices do I have if I don’t take part in this research study?” should 
always be used in their entirety if possible.  Editorial changes to these sections may be made as long as 
they do not change information or intent.  If the institutional IRB insists on making deletions or more 
substantive modifications to these sections, they may be justified in writing by the investigator and 
approved by the IRB.  Under these circumstances, the revised language and justification must be 
forwarded to the Academic and Community Cancer Research United (ACCRU) Operations Office for 
approval before a patient may be registered to this study. 
 
Consent forms will have to be modified for each institution as it relates to where information may be 
obtained on the conduct of the study or research subject.  This information should be specific for each 
institution. 


Amendment 1 
9  
ACCRU-SC-1601 
Appendix II 
Page 1 of 1 
 
Appendix II 
Strong CYP3A4 Inhibitors/Inducers 
 
 
 
 
 
 
 
Strong CYP3A4 Inhibitors 
Strong CYP3A4 Inducers 
Antibiotics 
Clarithromycin 
Telithromycin 
Rifampin 
Rifabutin 
Antidepressants 
Nefazodone 
 
Antifungals 
Itraconazole 
Ketoconazole 
 
Protease Inhibitors 
Posaconazole 
Voriconazole 
Atazanavir 
Boceprevir 
Darunavir 
Delavirdine 
Indinavir 
Lopinavir 
Nelfinavir 
Ritonavir 
Saquinavir 
Tipranavir 
 
Anticonvulsants 
 
Carbamazepine 
Phenobarbital 
Phenytoin 
Fosphenytoin 
Primidone 
Other 
 
St John’s wort 


Amendment 1 
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Appendix III 
Page 1 of 1 
 
Appendix III 
Khorana Score 
 
 
The Khorana score is a simple validated risk model for predicting rates of VTE in cancer outpatients 
receiving chemotherapy, using baseline clinical and laboratory variables.   This risk model incorporates 
five predictive variables for VTE including: site of cancer (2 points for very high-risk site; 1 point for 
high risk site), platelet count ≥ 350 x 109/L (1 point), hemoglobin < 10 g/dL and/or use of erythropoiesis 
stimulating agents (1point), leukocyte count > 11x109/L (1 point), and body mass index ≥ 35 kg/m2 (1 
point) (1).  Based on their score, patients are then divided into low (0 points), intermediate (1 -2 points) or 
high risk (≥ 3 points).  Rates of venous thromboembolism over the ensuing 2.5 months were 0.3 - 0.8% in 
low-risk, 1.8 - 2% in intermediate-risk, and 6.7-7.1% in high-risk groups.   
 
Very high risk sites include stomach and pancreas cancers.  High risk cancer sites include lung, 
lymphoma, gynecologic, bladder, and testicular cancers.   
 
Risk assessment can be promptly carried out using an online calculator: 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW.  Development and validation of a 
predictive model for chemotherapy-associated thrombosis.  Blood. 2008 May 15;111(10):4902-7. 
 
 
 


Amendment 1 
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Appendix IV  
Page 1 of 1 
 
Appendix IV 
Non CTCAE Bleeding Grading Scale 
Based on The International Society on Thrombosis and Haemostasis (ISTH) guidelines 
 
 
Grade 
Symptom 
1 
Minor bleed 
Minor bleeding is defined as overt bleeding that did not meet criteria for 
major bleeding or clinically relevant non-major bleeding. 
 
2 
Non-Major bleed 
Clinically relevant non-major bleeding is defined as overt bleeding not 
meeting the criteria for major bleeding but associated with medical 
intervention, an unscheduled contact with a member of the health care 
team, or temporary cessation of study treatment. 
 
3 
Major bleed 
Major bleeding is defined as overt bleeding plus a hemoglobin decrease 
of ≥ 2 g/dL or transfusion of ≥ 2 units of packed red blood cells, or 
intracranial, intraspinal, intraocular, retroperitoneal, pericardial or fatal 
bleeding. 
 
 
 


Amendment 1 
 
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Appendix V 
Page 1 of 2 
Appendix V 
Phone Contact Sheet 
Telephone Script 
 
 
Protocol Title: A Phase III, Controlled, Randomized, Double-Blind Study Evaluating the Safety of Two 
Doses of Apixaban for Secondary Prevention of Cancer Related Venous Thrombosis in Subjects Who 
Have Completed at Least Six Months of Anticoagulation Therapy 
IRB #:  
Principal Investigator: Robert McBane, MD 
 
 
“Good morning/afternoon.  This is ___________________ calling from [name of institution].  
 May I speak to__________?” 
 (If participant is there proceed to the following:) 
 
 “I would like to ask you a few questions regarding your blood thinner medication, apixaban and the 
clinical trial in which you have been enrolled. This will allow us to gather very important information 
about the safety and benefit of using this medication in treating and preventing blood clots.”   
 
“I would like to ask these questions related to our study after confirming your name” 
Patient Name __________________________________________ 
 
 
1. Over the past month, have you missed any doses of your blood thinner medication? 
____ Yes  
If yes, approximately how many doses do you estimate that you have missed? ___________ 
If yes, why was the dose missed? ________________________________________________   
____ No, I have not missed any doses of medication 
 
 
 
2. Over the past month have you had another blood clot problem? 
____ Yes, a DVT (must contact local medical doctor to obtain documentation) 
____ Yes, a PE 
____ Yes, both a DVT and a PE 
____Yes, something else (e.g. an arterial clot).  Please describe: _____________________________ 
____ No, I have not had any more clots.  
 
 
3. While you have been taking this medication as recommended have you experienced any major 
bleeding which required hospitalization or blood transfusion? 
____ Yes. Please describe_____________________________ 
____ No  
 
Any bleeding other than that from an injury? (For example a spontaneous bloody nose.) 
____ Yes, Please describe_____________________________ 
____ No  
 
 


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Appendix V 
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4. Over the past month, have you undergone any surgeries or invasive procedures?  
____ Yes  
If yes, what type of surgery/procedure did you have?  _____________________ 
What was the date of the procedure?  __ __-___ ___-___ ___ (MM-DD-YY) 
____ No, I have not had any surgeries or procedures 
 
5. Which of the following best applies to your current activity rating: ________ 
A. Fully active, able to carry on all activities before your disease  without restriction 
B. Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature, e.g., light house work, office work 
C. Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours 
D. Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
E. Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
 
6. What is your current weight?  ________ 
 
7. Have you started any new medications?  List these __________________ 
 
8. Have you had any new leg swelling? 
___ Yes 
i. If yes, suggest that the patient see their medical provider 
____No, I have not had any new leg swelling. 
 
9. Have you had any new chest pain or shortness of breath? 
___ Yes 
i. If yes, instruct  the patient to call 911/go to ER.  
___ No, I have not had any new chest pain or shortness of breath. 
 
 
Do you have any questions for me? 
 
 
 “Thank you for participating in our study.  
 
NOTE: If there is any evidence of bleeding or clotting, review this with the attending clinician and 
obtain documentation from the local healthcare provider if patient gave consent.  
 


Amendment 1 
 
ACCRU-SC-1601 
 
Appendix VI 
Patient Education Material  
 
Deep Vein Thrombosis and Pulmonary Embolism 
(©2016 Mayo Foundation for Medical Education and Research) 
See next page 
 


Amendment 1 
 
ACCRU-SC-1601 
Appendix VII 
Page 1 of 1 
 
 
Appendix VII 
 
Patient Compliance Information 
 
1. Over the past month, have you missed any doses of your blood thinner medication? 
____ Yes,  
____ If yes, approximately how many doses do you estimate that you have missed? 
____ If yes, why was the dose missed? 
____ No, I have not missed any doses of medication