Conditions: Cerebral Vein Thrombosis Deep Vein Thrombosis Gonadal Thrombosis Hepatic Thrombosis Malignant Neoplasm Mesenteric Thrombosis Metastatic Malignant Neoplasm Portal Vein Thrombosis Pulmonary Embolism Renal Vein Thrombosis Splenic Thrombosis Venous Thromboembolism
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 300
Healthy volunteers: no

Brief summary:
This randomized phase III trial studies the side effects of and compares apixaban and dalteparin in reducing blood clots in patients with cancer-related venous thromboembolism. Venous thromboembolism is a condition in which a blood clot forms in a vein and then breaks off and moves through the bloodstream. Patients with cancer are at increased risk for venous thromboembolism. Apixaban and dalteparin are drugs used to prevent blood clots from forming or to treat blood clots that have formed. It is not yet known whether apixaban or dalteparin is more effective in reducing blood clots in patients with cancer related venous thromboembolism.

ADAM-VTE

Detailed description:
PRIMARY OBJECTIVES:

I. Any episode of major bleeding including fatal bleeding.

SECONDARY OBJECTIVES:

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

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

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive apixaban 10 mg orally (PO) twice daily (BID) on days 1-7 and lower-dose apixaban 5 mg PO BID on days 8-180.

ARM II: Patients receive dalteparin 200 international units (IU)/kg/day subcutaneously (SC) once daily (QD) on days 1-30 and lower-dose dalteparin 150 IU/kg/day SC QD on days 31-180.

After completion of study treatment, patients are followed up at 3 months.

Arms:
arm 1: Patients receive apixaban 10 mg PO BID on days 1-7 and lower-dose apixaban 5 mg PO BID on days 8-180. arm 2: Patients receive dalteparin 200 IU/kg/day SC QD on days 1-30 and lower-dose dalteparin 150 IU/kg/day SC QD on days 31-180.

Interventions: intervention 1: Apixaban intervention 2: Dalteparin intervention 3: Questionnaire Administration
Intervention descriptions: intervention 1: Given PO intervention 2: Given SC intervention 3: Ancillary studies

Protocol document:
Prot_SAP_000.pdf: 
       3 
ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
ACCRU version date:   April 22, 2016 
    
 
Academic and Community Cancer Research United (ACCRU) 
 
A Phase III, Randomized, Open label Study Evaluating the Safety of Apixaban in Subjects with 
Cancer Related Venous thromboembolism  
 
For any comminications regarding this protocol, please contact the person indicated on the Protocol 
Resource Page. This is a stand-alone document found on the ACCRU web site (www.ACCRU.org) 
 
  
 
ACCRU Study Chairs: 
Robert D. McBane, M.D.  
 
 
 
 Mayo Clinic 
 
 
200 First Street SW 
 
 
 
Rochester, MN 55905 
 
 
 
507/284-4565    
 
 
 
 Mcbane.robert@mayo.edu  
 
 
   
 
  
 
Charles L. Loprinzi, M.D.  
 
 
 
Mayo Clinic 
 
 
 
200 First Street SW 
 
 
 
Rochester, MN 55905 
 
 
 
507/284-4565      
 
 
 
cloprinzi@mayo.edu  
  
    
    Co-Chair:  
 
 
   
  
  Statistician:  
 
   
 
 
 
 
 
 
 
 
 
 
 
  
Drug Availability   
Drug Company Supplied:  Apixaban (Eliquis®) IND Exempt; 
 
Dalteparin (Fragmin®) (commercial supply) 
 
√ Study contributor(s) not responsible for patient care. 
 
Research Coordinating Center 
Academic and Community Cancer Research United 
200 First Street Southwest 
Rochester, MN 55905 
FAX# 507-538-0906 
Document History 
(effective date) 
Pre-activation ACCRU 
September 11, 2015 
Activation 
      November 20, 2015 
Amendment 1 
December 10, 2015 
Amendment 2 
April 22, 2016 
Amendment 3 
December 01, 2017 
This trial will be conducted in compliance with the protocol, GCP and the applicable 
regulatory requirement(s). (ICH E6 section 6.2.5) 
 


 
2  
ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
  
 
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 
 
 
  
 
  
   
   
    
    
  
 
 
 
 


       3 
ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
ACCRU version date:   April 22, 2016 
 
Schema 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cycle = 30 days 
Observation = 3 months  
Note that ‘cycle’ information is a data management tool to facilitate remote data entry. 
 
 
 
 
 
Generic name:    Apixaban  
Brand name(s):   Eliquis® 
ACCRU Abbreviation:   APIXABAN 
 
  
Availability:   Biologics, Inc. 
Generic name:    Dalteparin 
Brand name(s):  Fragmin® 
ACCRU Abbreviation:   DALTEPARIN   
  
Availability:    Biologics, Inc. 
Arm A 
Apixaban10 mg by mouth 
  twice daily for 7 days followed  
by 5 mg twice daily for a  
total of 6 months  
  
Arm B 
Dalteparin injection 
200 IU/kg/day for 30 days 
followed by 150 IU/kg/day for a 
total of 6 months 
Weight based dosing 
 
Randomization   
 
Observation (3 months) 
Unacceptable adverse events or 
patient refusal at any time →  Off 
Study  
 
Off Study  


 
4  
ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
  
1.0 
Background   
 
1.1 
Treatment  
 
The association between cancer and venous-thromboembolism (VTE) is strong and well 
established (1-4).  Active cancer with and without chemotherapy increases the risk of 
VTE by 5 to 6 fold (5). Furthermore, active cancer accounts for about 20% of the VTE 
burden occurring in a community (6). VTE is the second most common cause of death 
among patients with cancer (7). Indeed, cancer patients with VTE have a 2-fold or greater 
increase in mortality compared with cancer patients without VTE, even after adjusting for 
stage (8,9).  Nearly half of the patients with cancer associated VTE have distant 
metastasis at the time of VTE diagnosis (8). The incidence of cancer in patients with 
recurrent idiopathic VTE is higher than in patients with secondary VTE (3).   
The management of patients with active cancer can be particularly challenging given 
their increased propensity for both VTE recurrence as well as major bleeding (10-15). 
Patients with cancer pose a special challenge because of an increased risk of thrombosis 
due to cancer-specific prothrombotic activity, hormonal therapy, angiogenesis inhibitors 
and radiotherapy, and the presence of chronic indwelling central venous catheters 
(10,14,16). At the same time, cancer patients are at increased risk of major bleeding due 
to chemotherapy-related hepatic dysfunction, kidney injury, thrombocytopenia, and 
tumor friability (15,16).   
 
There have been four important treatment trials of cancer associated VTE (17-22).  The 
CLOT trial randomized 672 patients with active cancer and acute VTE to receive either 
low molecular weight heparin (LMWH) (Dalteparin 200 IU/kg/day for 1 month followed 
by 150 IU/kg/day for 5 months) or adjusted dose warfarin (18).  At the end of the six-
month study period, recurrent thromboembolism was 17% in the oral-anticoagulant group 
and 9% in the dalteparin group (hazard ratio, 0.48; P=0.002). There was no significant 
difference between groups in the rate of major bleeding (dalteparin 6% vs. warfarin 4%).  
Overall mortality rates did not differ between treatment arms. Substudy analysis of the 
CLOT trial however revealed improved survival in cancer patients without metastasis 
receiving dalteparin compared to warfarin (19).  For patients with metastatic disease, 
there was no difference in survival by treatment allocation.  In a separate study, 146 
cancer patients with active VTE were randomized to receive enoxaparin (1.5mg/kg/day) 
or warfarin for 3 months (20). During the 3-month treatment period, patients assigned to 
receive warfarin experienced more major hemorrhage or recurrent thromboembolism 
(21.1%) compared to enoxaparin (10.5%) however this did not reach statistical 
significance (P = .09).  Using a time to major event (recurrent VTE or major bleed) 
analysis, enoxaparin was however more effective than warfarin (p=0.04).   The 
ONCENOX investigators compared enoxaparin (enoxaparin 1.0 mg/kg every 12 hours 
for 5 days, followed by 1.0 mg/kg daily or 1.5 mg/kg daily for 175 days) to warfarin in 
122 adults with active malignancy (21).  Enoxaparin treatment was feasible, generally 
well tolerated, and effective for a 180-day period in the secondary prevention of venous 
thromboembolic events in patients with active malignancy.  There were no significant 
differences in major and minor bleeding rates between treatment groups. The LITE 
investigators compared once daily subcutaneous tinzaparin to warfarin in 200 adult 
cancer patients with acute VTE (22).  At 12 months, warfarin treated patients had greater 
recurrent venous thromboembolism (16% versus 7%) compared to those receiving 
LMWH (P=.044; risk ratio=0.44; absolute difference -9.0; 95% CI -21.7 to -0.7).  Major 
bleeding rates did not differ between the two groups.    


 
5  
ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
  
Based on these four treatment trials in cancer 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 (17).  Anticoagulants are 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 either once 
or twice daily 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 urine 
and 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 (23).  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 
composite of major plus non-major yet clinically relevant bleeding were significantly 
lower for patients receiving apixaban.  The Amplify Extend investigators randomized 
2482 patients with VTE who had recently completed 6 – 12 months of anticoagulation to 


 
6  
ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
  
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 (24).  
 
Despite these trial results, apixaban is not currently recommended for cancer related VTE 
treatment or 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 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 order to gain guideline endorsement, apixaban must be assessed in a randomized 
controlled trial compared to the current gold standard anticoagulation standard for cancer 
patients.  The current standard of care for these patients is LMWH, and specifically 
dalteparin.  Moreover the comparator in AMPLIFY was warfarin which is not guideline 
endorsed therapy in this setting.   Second, opinion leaders in the field often recommend 
against the use of factor Xa inhibitors in cancer patients with VTE (personal 
communication).  Third, 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 remains quite attractive. 
 
Beyond apixaban, other factor Xa inhibitors have proven efficacy in VTE treatment.  For 
example, rivaroxaban, an oral direct factor Xa inhibitor, has a time to peak concentration 
of 2-4 hours with an elimination half-life of 7-11 hours.  The EINSTEIN DVT trial 
randomized 3449 patients with symptomatic DVT to oral rivaroxaban alone (15 mg twice 
daily for 3 weeks, followed by 20 mg once daily) or enoxaparin followed by warfarin (or 
acenocoumarol) (25).  The EINSTEIN-PE investigators randomized 4832 patients with 
acute PE to either rivaroxaban or enoxaparin/warfarin (26).  In both trials, rivaroxaban 
was initiated without parenteral anticoagulant bridging or monitoring and was non-
inferior to enoxaparin/warfarin for safety and efficacy.  After completing the initial 
treatment phase, 1196 patients were re-randomized to either continued rivaroxaban 20 mg 
daily or placebo (20).   Continued rivaroxaban reduced recurrent thrombotic events 
compared to placebo (1.3% vs. 7.1%) yet with similar bleeding rates (0.7% vs. 0%).  In 
the Einstein trials, 321 patients with active cancer were randomized to rivaroxaban 
therapy.  The interpretations of these data are limited whereby we have no data on the 
types of cancer, presence of metastasis and type of chemotherapy used.  Moreover, like 
AMPLIFY, the comparator in these trials was warfarin and not LMWH as endorsed by 
the guidelines.   
 
Either factor Xa inhibitors may therefore be chosen for a cancer related VTE therapy trial 
compared to LMWH.  Apixaban however is a contender for first line therapy for several 
reasons. First, the twice daily dosing of apixaban, although maybe less convenient, may 
improve efficacy and safety.  The peak levels are anticipated to be lower than once daily 
dosing thus decreasing potential bleeding (32).  The trough levels are anticipated to be 
higher thus improving efficacy with continued presence of drug relative to once daily 
dosing.  Second, the multiple routes of elimination are attractive particularly in these 
patients who may intermittently suffer renal or hepatic toxicities related to the underlying 
disease and cancer treatment.  Third, apixaban has been shown to have extremely low 
rates of major bleeding.  This is particularly attractive in cancer patients who are at 
increased risk of bleeding with thrombocytopenia, coagulopathy, tissue friability and 
cancer related invasive procedures.    


 
7  
ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
  
  
1.4 
Dose Rationale and Risk/Benefits 
 
The AMPLIFY investigators compared apixaban (10 mg twice daily for 7 days followed 
by 5 mg twice daily for 6 months) to enoxaparin/warfarin in 5395 patients with acute 
VTE (23).  At the 6 month follow up, recurrent VTE occurred in 2.3% in the apixaban 
group compared to 2.7% in the enoxaparin/warfarin group meeting the criteria for 
noninferiority (relative risk 0.84 (95% CI 0.60-1.18; p<0.001).  Similar outcomes were 
noted regardless of whether the initial event was a DVT or PE.  Major bleeding occurred 
in 0.6% of the apixaban compared to 1.8% of the conventional-therapy group.  The 
difference in major bleeding was superior for apixaban (relative risk 0.31 (95% CI, 0.17-
0.55; P<0.001).  The AMPLIFY-Extend investigators then compared prolonged treatment 
with apixaban (2.5 mg or 5 mg, twice daily) with placebo in 2486 patients who had just 
completed 6 – 12 months of anticoagulation treatment for an acute VTE (24).  Recurrent 
VTE or death from VTE was significantly lower in those patients assigned to either 2.5 
mg (1.7%) or 5 mg (1.7%) twice daily apixaban compared to placebo (8.8%).  Major 
bleeding rates were similarly low for apixaban 2.5 mg (0.2%), apixaban 5 mg (0.1%) and 
placebo (0.5%).  Based on these data from the AMPLIFY trials, apixaban 10 mg twice 
daily for 7 days followed by 5 mg twice daily will be the prescribed dose for this trial.   
 
The CLOT trial randomized 672 patients with active cancer and acute venous 
thromboembolism to receive either LMWH (dalteparin 200 IU/kg/day for 1 month 
followed by 150 IU/kg/day for 5 months) or adjusted dose warfarin (18).  At the end of 
the six-month study period, recurrent thromboembolism was 17% in the oral-
anticoagulant group and 9% in the dalteparin group (hazard ratio, 0.48; P=0.002). There 
was no significant difference between groups in the rate of major bleeding (dalteparin 6% 
vs. warfarin 4%).  Therefore, based on the CLOT trial, and the Fragmin USPI 
recommended dosing, dalteparin 200 IU/kg/day for 1 month followed by 150 IU/kg/day 
will be the comparator drug and dosing schedule prescribed.   
 
1.5 
General Design  
 
 
This is a multicenter, randomized, open-label, 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 twice daily automated screening of vascular 
radiology ultrasound and computed tomography reports.  Interested qualified subjects 
will be consented and offered participation in this trial.  Pre-randomization 
anticoagulation treatment is allowed up to a maximum of 7 days.  After randomization, 
patients allocated to apixaban will receive 10 mg twice daily for 7 days, followed by 5 
mg twice daily. Patients allocated to the comparator will receive dalteparin 200 
IU/kg/day for 1 month followed by 150 IU/kg/day.  Allocation to treatment will be done 
centrally.  Once consent has been obtained baseline values will be established and 
subjects will begin treatment and follow-up for 6 months.   
 


 
8  
ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
  
The principal safety outcome is major bleeding. All episodes of 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. 
  
  
2.0 
Goals    
 
2.1 
Primary 
 
2.11    The primary safety endpoint will include: any episode of major bleeding 
including fatal bleeding.  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. 
 
• 
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 
 
2.21  
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.   
 
• 
Fatal PE:  PE based on objective diagnostic testing, autopsy, or death which 


 
9  
ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
  
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.  
 
2.22 
The secondary safety endpoint will include the combined endpoints of any 
episode of major bleeding including fatal bleeding or any episode of clinically 
relevant non-major bleeding.   
 
3.0 
Patient Eligibility    
 
3.1 
Inclusion Criteria   
 
3.11 
Age ≥18 years. 
 
3.12 
Confirmed acute lower extremity or upper extremity (jugular, innominate, 
subclavian, axillary, brachial) DVT, PE, splanchnic (hepatic, portal, splenic, 
mesenteric, renal, gonadal), or cerebral vein thrombosis. 
 
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 ≥ 60 days. 
 
3.15 
ECOG Performance Status (PS) of 0, 1, or 2.  (Form is available on the ACCRU 
web site 
https://www.accru.org/accru/forms/NonProtocolSpecificForms/index.html).  
 
3.16 
The following laboratory values obtained ≤30 days prior to randomization.   
• 
Platelet count ≥50,000/mm3 
• 
Alanine aminotransferase (ALT) or Aspartate transaminase (AST) ≤3 x ULN 
• 
INR ≤1.6 (if not taking anticoagulant therapy) 
• 
Calculated creatinine clearance must be ≥30 ml/min using the Cockcroft-
Gault formula below: 


 
10  
ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
  
 
3.17 
Negative serum or urine pregnancy test done ≤24 hours prior to randomization, 
for women of childbearing potential only. 
Note:  A Women 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 complete questionnaire(s) by themselves or with assistance.    
 
3.19a 
Ability to provide informed written consent. 
 
3.19b Willing to return to enrolling institution for follow-up (during the Active 
Monitoring Phase of the study). 
 
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. 
 
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) 


 
11  
ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
  
At a minimum, subjects must agree to the use of one method of highly effective 
contraception as listed below: 
 
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. Female subjects must continue to have pregnancy tests. 
Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete 
abstinence. 
 
3.22 
Treatment with an anticoagulant for more than 7 days for the current blood clot, 
prior to randomization.   
 
3.23 
Active bleeding.  
 
3.24 
Severe hypersensitivity reaction to apixaban, dalteparin, heparin or pork products 
(e.g., anaphylactic reactions). 
 
3.25 
Use of the following CYP3A4 inducers:   rifampin, rifabutin, carbamazepine, 
efavirenz, phenobarbital, phenytoin, fosphenytoin, primidone, and St. John’s 
wort [see list in appendix II]). 
 
3.26 
Thienopyridine therapy (clopidogrel, prasugrel, or ticagrelor) that will be 
continued on study. 
 
3.27 
Severe liver disease (known cirrhosis Childs Pugh class B or C), or active 
hepatitis.  
 
3.28 
Use of a Factor Xa Inhibitor (e.g. apixaban, rivaroxiban, or edoxaban) ≤3 months 
prior to randomization.    
 
3.29a 
Treatment of a thromboembolic event ≤6 months prior to randomization.  
 
3.29b  Documented venous thromboembolism while on therapeutic anticoagulation 
(“anticoagulation failure”). 
 
3.29c 
Mechanical heart valve. 


 
12  
ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
  
 
3.29d Documented hemorrhagic tendencies. 
 
3.29e 
Bacterial endocarditis. 
 
3.29f 
History of heparin induced thrombocytopenia. 
 
3.29g 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 
• 
Overt major bleeding at the time of randomization 
• 
Gross hematuria at the time of randomization 
 
   


13 
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
ACCRU version date:   April 22, 2016 
4.0 
Test Schedule 
 
Active Monitoring Phase 
 
 
 
Tests and procedures 
 
≤14_days 
prior to 
registration 
(baseline) 
 
 Every 30 
days after the 
start of 
treatment 
(± 1 week)   
 
 
End of  
treatment  
 
 
Observation:  
3 months  
after the 
completion 
of treatment  
(as defined 
per  
protocol) 
(± 1 week)   
History and exam (including weight and   
bleeding assessment, see App. IV) 
X 
X6 
  
  
ECOG PS 
X 
X  
  
 
Height 
X 
  
 
 
Adverse event assessment 
X 
X 
  
X  
Hematology: 
• CBC  
• 
Platelets  
 
X1 
 
X 
 
X5 
 
 
INR 
X1 
 
 
 
Chemistry:   
• SGOT (AST) or ALT 
• Creatinine  
 
X1 
 
X 
  
 
X5 
 
 
Selected concomitant meds  (see CRF for this 
form) 
X 
X 
  
  
US, CT, MRI, or VQ scan to confirm acute 
lower extremity or upper extremity DVT, PE or 
splanchnic vein thrombosis  
 
X 
       
        
 
  
 
 
Pregnancy test2 
X 
 
 
 
Patient Questionnaire Booklets3 (App.VI, VII) 
• Mayo Blood Thinner Questionnaire  
• Bruising Question   
 
X4 
 
X 
 
  
Patient Phone Call (including bleeding 
assessment, see App. IV and  VIII) 
 
 
X 
X  
1. ≤30 days prior to registration. 
2.  For women of childbearing potential only.  Must be done ≤24 hours prior to randomization.  
3.    Patient questionnaire booklets must be used; copies are not acceptable for this submission. 
4. Must be completed after registration and prior to treatment.  
5.   If feasible. 
6. If it is not feasible for the patient to return to the enrolling center for the physical examination, a 
detailed history will be obtained by phone using a structured interview (see Appendix X).  
  
 
  


 
14  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
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). 
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 
.  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 


 
15  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
• 
Existence of a signed authorization for use and disclosure of protected health 
information   
 
 
 
6.14 
Treatment cannot begin prior to registration and must begin ≤5 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 
All required baseline symptoms (see Section 10.3) must be documented and 
graded. 
 
6.17 
Treatment on this protocol must commence at an ACCRU institution under the 
supervision of a health care professional. 
6.18 
Study drug is available on site.  
 
6.19 
Patient questionnaire booklet is available on site; copies are not acceptable for 
this submission.  
 
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 
• 
Dalteparin  
 
7.0 
Protocol Treatment 
 
 
7.1 
Treatment Schedule - Use actual weight (Kg) 
Arm 
Agent 
Dose Level 
Frequency  
Route 
A 
Apixaban* 
 
10 mg    
Twice daily days 1-7  
Oral  
5 mg    
Twice daily days  
8-180  
B 
Dalteparin*  
  
200 IU/kg/day  
Once daily for days 
1- 30 
Subcutaneous 
Injection** 
150 IU/kg/day 
Once daily for days 
31-180  
*If a dose of apixaban or dalteparin is not taken at the scheduled time, the dose should be taken as 
soon as possible on the same day and the prescribed dosing schedule should be resumed.  The 
dose should not be doubled to make up for missed doses.   
 
** The dosage will be calculated on the patient’s current weight in kilograms, rounded to the 
nearest whole kilogram. The syringe dose will be chosen based on the weight adjusted calculation 
based on the table 7.11. The patient will be taught by on site nursing staff how to administer the 
medication, and also how to “waste” from each syringe such that the appropriate weight adjusted 


 
16  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
dose is delivered.    
 
 
7.11 
 
 
 
 
Month 1:   200 IU/kg SQ daily 
 
Body Weight 
(kg) 
Dalteparin Dose (IU) once 
daily 
≤ 40 
7,500 
41-56 
10,000 
57-68 
12,500 
69-82 
15,000 
83-94 
18,000 
95-107  
10,000 & 10,000 =20,000 
108-120 
18,000 & 5,000 = 23,000 
121-133 
15,000 & 10,000 = 25,000 
134-147 
18,000 & 10,000 = 28,000 
148-160 
15,000 & 15,000 = 30,000 
≥161 
200 IU/kg SQ daily 
 
   
 
Months 2-6:   150 IU/kg SQ daily 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.12 
Dalteparin therapy is weight based dosing.  Monthly weights should be 
performed and communicated with the study coordinator. For patients 
experiencing more than 10% weight loss or gain, the dose of dalteparin will be 
adjusted to current body weight. Round according to table 7.11.   
 
7.13 
Scheduled visits should include a standardized assessment of the signs and 
symptoms of 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 IX). All suspected 
episodes of recurrent thrombosis should be investigated with the use of objective 
Body Weight 
(kg) 
Dalteparin Dose (IU) once 
daily 
≤ 40 
5,000 
41-57 
7,500 
58-77 
10,000 
78-92 
12,500 
93-110 
15,000 
111-130 
18,000 
131-141 
10,000 & 10,000 = 20,000 
142-160 
18,000 & 5,000 = 23,000 
≥161 
150 IU/kg SQ daily 


 
17  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
tests, according to pre-specified diagnostic algorithms. 
 
 
7.2 
Post protocol completion: Anticoagulation decision algorithm 
 
7.21 
Following the 6 months of protocol completion, a decision regarding 
anticoagulation continuation will be clinically determined. (31)  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.  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: 
continued LMW heparin (dalteparin or enoxaparin), apixaban (or other oral novel 
direct factor inhibitors 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.      
 
7.22 
For surveillance purposes, participants will be contacted by telephone at 3 
months post protocol completion to determine the incidence of thrombosis 
recurrence, major bleeding and clinically relevant non-major bleeding.   
 
8.0 
Dosage Modification Based on Adverse Events  
 
8.1  
Apixaban is cleared through several mechanisms including renal clearance, hepatic 
metabolism, and fecal excretion.  Dalteparin is excreted through renal clearance.  For 
both drugs, severe thrombocytopenia, liver and renal failure represents an increased 
bleeding risk.  For these purposes, patients will require monthly assessment of complete 
blood counts (CBC), renal function (creatinine clearance calculation), and liver function 
(ALT).  Each of these measures is clinically indicated for anticoagulation management.   
 
 
Patients with calculated creatinine clearance ≤30 ml/min (using the Cockcroft-Gault 
formula) must discontinue treatment and go to observation. They may get alternative 
anticoagulation treatment per the attending physician judgment. 
   
 
For patients who are receiving concomitant use of strong CYP3A4 and/or P-glycoprotein 
inhibitors (i.e. ketoconazole, itraconazole, ritonavir, or clarithromycin; see appendix II 
for a list of strong CYP3A4 inhibitors), the dose of apixaban will be reduced to 2.5 mg 
twice daily.  Upon discontinuation of the strong CYP3A4 inhibitor, then the full dose of 
apixaban 5 mg twice daily should be instated/reinstated.   
 
For patients receiving a strong CYP3A4 inducer (appendix II), alternative agents within 
the specific class of drug should be sought.  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 


 
18  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
thrombocytopenia (25,000-50,000/microliter), apixaban dose reduction to 2.5 mg twice 
daily is necessary.  For thrombocytopenia (< 25,000/microliter), apixaban will be held  
 
until platelet count recovers.  Once the platelet count improves, the apixaban dose should 
be adjusted accordingly.      
 
Dalteparin therapy is weight based dosing.  Monthly weights should be performed and 
communicated with study staff.  For patients experiencing more than 10% weight loss or 
gain, the dose of dalteparin will be adjusted to current body weight.     
 
The dalteparin dose should be adjusted for patients experiencing kidney injury.  An 
exclusion criterion for study enrollment is a creatinine clearance <30 ml/min.  For those 
patients already enrolled who then develop worsening kidney function, the dalteparin 
dose will then be adjusted.  For creatinine clearance between 15 and 30 ml/min, the dose 
of dalteparin should be reduced.  During the first month of treatment when the patient is 
receiving 200IU/kg, the dose will be reduced to 150 IU/kg.  During subsequent months, 
the dose of 150 IU/kg will be reduced to 100 IU/kg.  Once the creatinine clearance 
improves to values > 30 ml/min, the standard dosing will be reintroduced.   
 
For patients with severe kidney injury defined as creatinine clearance < 15 ml/min, 
dalteparin should be held and the patient should stop the study treatment and receive 
treatment per the attending physician.    
 
For thrombocytopenia (> 50,000/microliter), no dose adjustment is necessary. For 
thrombocytopenia (25,000-50,000/microliter), dalteparin dose reduction to 5000 IU/day 
is necessary.   For thrombocytopenia (< 25,000/microliter), dalteparin will be held until 
platelet count recovers.  Once the platelet count improves, the dalteparin dose should be 
adjusted accordingly.      
     
8.2 
Patients requiring an 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. 
Dalteparin dose will be reduced to 100 IU/kg and given on the morning prior to the 
procedure date with no drug given on the procedure date; 
(3) Post procedure, the patient could receive prophylactic apixaban (2.5 mg twice daily) 
or dalteparin (5000 IU once daily) dosing for 48 hours; the first prophylactic dose will be 
given 24 hours after the procedure;  
(4) Therapeutic apixaban or dalteparin will be withheld until 72 hours after the procedure 
and not initiated until adequate hemostasis is confirmed.   
 
If apixaban or dalteparin treatment is temporality held, the reason will be recorded on the 
CRF and the patient can go back on study for up to day 180 of the original treatment 
schedule.  
 
9.0 
Ancillary Treatment/Supportive Care 
 
9.1 
Concomitant use of strong CYP3A4 inhibitors (e.g., HIV protease inhibitors, systemic 
ketoconazole (appendix II) should be discouraged.  In the case of clinical necessity, for 


 
19  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
those patients randomized to apixaban, the dose of apixaban will be reduced to 2.5 mg 
twice daily while the CYP3A4 inhibitor is given.   
 
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. 
 
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. 
 
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: 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm)     
 
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 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. 


 
20  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
 
• 
Unexpected AEs are those not listed in the agent-specific information 
provided in Section 15.0 of the protocol. 
 
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). 
 
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. 


 
21  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
 
• 
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. 
  
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 


 
22  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
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 within 24 hours and in accordance with 
SAE reporting procedures. 
 
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 
(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 Drug Induced Liver Injury (DILI) 
 
Wherever possible, timely confirmation of initial liver-related laboratory 
abnormalities should occur prior to the reporting of a potential DILI 
event. All occurrences of potential DILIs, meeting the defined criteria, 
must be reported as SAEs. 
 
Potential drug induced liver injury is defined as  
1. AT (ALT or AST) elevation > 3 times upper limit of normal (ULN) 
 
 
 
AND 
2. Total bilirubin > 2 times ULN, without initial findings of cholestasis 
(elevated serum alkaline phosphatase), 
 
 
 
AND 
3. No other immediately apparent possible causes of AT elevation and 
hyperbilirubinemia, including, but not limited to, viral hepatitis, pre-
existing chronic or acute liver disease, or the administration of other 
drug(s) known to be hepatotoxic. 
 
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. 
 


 
23  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
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 
 
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. 
 
 


 
24  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
2.  Follow site-specific reporting guidelines. 
 
3.  Submit MedWatch form 3500A 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 
 or 
  and 
will also forward to Pfizer via
.     
 
4.  The ACCRU SAE Coordinator will forward to 
 as 
appropriate. The ACCRU IND Coordinator will assist the sponsor-investigator in notifying 
the FDA if required.  
 
 
EVENT TYPE 
REPORTING PROCEDURE 
Other Grade 4 or 5 Events 
and/or Any Hospitalizations 
During Treatment Not 
Otherwise Warranting an 
Expedited Report 
 
 
Notification form: Grade 4 or 5 Non-AER Reportable Events/ 
Hospitalization Form to ACCRU within 5 working days1 
1.   If FDA Form 3500A (MedWatch) was completed, this form need not be completed. 
 
10.5 
Other Required Reporting 
 
10.51 Adverse events to be graded at each evaluation and pretreatment symptoms/conditions to 
be evaluated at baseline per the CTCAE v4.0 grading unless otherwise stated in the table 
below: 
 
 
System Organ 
Class (SOC) 
 
Adverse event/Symptoms 
 
Baseline 
Each 
evaluation 
Non CTCAE 
Grading Scale  
(major bleeding 
scale based on 
ISTH) 
See appendix IV 
Vascular disorder 
Other, specify:  
Bleeding 
X 
X 
X 
General disorders and 
administration site 
conditions 
Injection site reaction   
    
 
X 
 
Investigations  
Decreased platelet count 
 
X 
X 
 
 
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. 


 
25  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
 
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 be submitted as a 
Grade 5 AE, with a CTCAE type and attribution 
assigned. 
 
10.55   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). 
 
10.56 Research Coordinating Center will reconcile the clinical database SAE cases 
received from ACCRU Sites with the SAE cases that have been transmitted to 
BMS Global Pharmacovigilance (GPV&E). Frequency of reconciliation will 
occur no more frequently than quarterly for a maximum of twelve (12) 
reconciliations and will occur no less than once prior to study database lock. 
BMS GPV&E will e-mail upon request from the investigator, the GPV&E 
reconciliation report. Requests for reconciliation should be sent to 
aepbusinessprocess@bmscom. The data elements listed on the GPV&E 
reconciliation report will be used for case identification purposes. If the 
investigator determines a case was not transmitted to BMS GPV&E, the case will 
be sent immediately. 
 
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 
A patient is deemed a major violation, if protocol requirements regarding treatment in 
cycle 1 of the initial therapy are severely violated that evaluability for primary end point 
is questionable.  All data up until the point of confirmation of a major violation must be 
submitted.  The patient will go off study.   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.  


 
26  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
13.3 
A patient is deemed a cancel if he/she 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. 
 
14.0 
Body Fluid Biospecimens – Not applicable   
 
15.0 
Drug Information 
 
 
15.1 
Apixaban (Eliquis®) IND Exempt  
• 
Package Insert is available on the ACCRU web site.  
 
 
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 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 nearly 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 urine and 
feces.  
 
 
15.12 Formulation: Apixaban (Eliquis®) tablets are available for oral administration 
 
in strengths of 2.5 mg and 5 mg of apixaban with the following inactive 
 
ingredients: anhydrous lactose, microcrystalline cellulose, croscarmellose 
 
sodium, sodium lauryl sulfate, and magnesium stearate. The film coating 
 
contains lactose monohydrate, hypromellose, titanium dioxide, triacetin, and 
 
yellow iron oxide (2.5 mg tablets) or red iron oxide (5 mg tablets). 
 
 
15.13 Preparation and storage: Store at room temperature 20°C to 25°C (68°F-77°F); 
excursions permitted between 15°C and 30°C (59°F-86°F).  Please see package 
insert.  
 
 
15.14 Administration:  Apixaban will be provided in bottles containing 74 tablets of 
 
 
5 mg for the first 30 days of treatment (28 tablets for days 1-7; 46 tablets for days 
8-30).   For subsequent months, patients will receive 74 tablets of 5 mg strength.   
 
 
 
Administer without regards to meals.  If patient is unable to swallow tablets 
whole, 2.5 or 5 mg tablets may be crushed and suspended in 60 mL of dextrose 
5% in water followed by immediate delivery through a nasogastric tube. 
Apixaban tablets may also be crushed and suspended in water, or 5% dextrose in 
water (D5W), or apple juice or mixed with apple puree and immediately 
administered orally. Crushed apixaban tablets are stable in water, D5W, apple 
juice, and apple puree for up to 4 hours.   
 
15.15 Appearance:  Yellow, round, biconvex, film-coated tablets with “893” debossed 
on one side and “5” on the other side. 
 
 
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. 


 
27  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
 
 
b)  Distribution – Plasma protein binding in humans is approximately 87%. The 
 
steady-state volume of distribution is approximately 21 L.  
 
 
c)  Metabolism – Approximately 25% of an orally administered apixaban dose is 
recovered in urine and feces as metabolitesApixaban is metabolized mainly via CYP3A4 
and to a lesser extent via CYP1A2, 2C8, 2C9, 2C19, and 2J2  
 
d) Excretion  Apixaban is eliminated in both urine and feces. Renal excretion 
accounts for about 27% of total clearance. 
 
 
e)  Half-life Elimination – approximately 12 hours 
 
 
15.17 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  
 
 
 
 
 
Strong Dual Inhibitors of CYP3 A4 and P-gp 
 
The dose if ELIQUIS should be decreased to 2.5 mg twice daily then when is 
coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-
gp.(e.g.; ketoconazole, itraconazole, ritonavir, or clarithromycin). 
 
 
In patients already taking ELIQUIS at a dose of 2.5 mg twice daily, avoid 
coadministration with strong dual inhibitors of both CYP3A4 and P-gp. 
 
 
Strong Dual Inducers of CYP3A4 and P-gp 
 
Avoid concomitant use of ELIQUIS with strong dual inducers of CYP3A4 and P-
gp (e.g. e.g., rifampin, carbamazepine, phenytoin, St. John’s wort) because such 
drugs will decrease exposure to apixaban. 
 
Coadministration of antiplatelet agents, fibrinolytics, heparin, aspirin, and 
chronic NSAID use increases the risk of bleeding. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
Please consult current drug reference sources for a complete list of potential drug 
 
interactions. 
 
15.18 Please consult the package insert for the most current and complete adverse event 
information. 
 
 
 
 
 
 
 
 
 
15.19a  Drug procurement:  Bristol Myers-Squibb will supply the drug to Biologics, Inc.  
Each participating ACCRU treating location will order the drug from Biologics, 
Inc.  Fax the Drug Order Request Form (found in the forms packet) to: 
Biologics, Inc. 
Attn. Clinical Research Services 
Fax:
 
 


 
28  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
Each participating ACCRU treating location will be responsible for monitoring 
the supply of apixaban and will use the Drug Order Request Form to order 
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   
• 
Assess patient’s concomitant medications including OTC, and herbal 
products. There are several drug to drug interactions that may interfere with 
the absorption of agent. Additionally, warn patient to avoid taking 
medication with any other anti-platelet agents (i.e. aspirin, NSAIDS, etc.) 
• 
Warn patients of risk of bleeding, (including serious life- threatening internal 
bleeding). Instruct patients to report these to the study team 
• 
Patients should discuss any procedures with the study team and/or any 
provider prior to proceeding, due to the risk of post procedure bleeding. 
• 
Rarely patients may have nausea, treat symptomatically and monitor for 
effectiveness 
• 
Rarely LFT’s may be elevated. Follow any monitoring as recommended by 
the study protocol.  
 
15.2 
Dalteparin (Fragmin®) Commercial supply   
 
Package Insert is available on the ACCRU web site.  
 
 
15.21 Background: Dalteparin is a low molecular weight heparin with antithrombotic 
properties. It acts by enhancing the inhibition of Factor Xa and thrombin by 
antithrombin. In humans, dalteparin potentiates preferentially the inhibition of 
coagulation Factor Xa, while only slightly affecting the activated partial 
thromboplastin time (APTT).   
 
Dalteparin is used for the prevention of deep vein thrombosis (DVT) which may 
lead to pulmonary embolism, in patients requiring abdominal surgery who are at 
risk for thromboembolism complications (eg, patients >40 years of age, obesity, 
patients with malignancy, history of DVT or pulmonary embolism, and surgical 
procedures requiring general anesthesia and lasting >30 minutes);  prevention of 
DVT in patients undergoing hip-replacement surgery; patients immobile during 
an acute illness; prevention of ischemic complications in patients with unstable 
angina or non-Q-wave myocardial infarction on concurrent aspirin therapy; in 
patients with cancer, extended treatment (6 months) of acute symptomatic venous 
thromboembolism (DVT and/or PE) to reduce the recurrence of venous 
thromboembolism. 
 
 
15.22 Formulation: Dalteparin sodium injection (Fragmin®) is available as single 
 
dose prefilled syringes in the following sizes: 2,500 IU/0.2 mL, 5,000 IU/0.2 mL, 
 
7,500 IU/0.3 mL, 12,500 IU/0.5 mL, 15,000 IU/0.6 mL, and 18,000 IU/0.72 
 
mL.  It is also available as a single-dose graduated syringe of 10,000 IU/1 mL,  
 
and is available as a multiple dose vial containing 95,000 IU/3.8 mL  
 
 
(25,000 IU/mL).   
 
 
Each prefilled syringe also contains Water for Injection and sodium chloride, 
when required, to maintain physiologic ionic strength. The prefilled syringes are 


 
29  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
preservative-free. Each multiple-dose vial also contains Water for Injection and 
14 mg of benzyl alcohol per mL as a preservative. The pH of both formulations is 
5.0 to 7.5 
 
15.23 Preparation and storage:  Store at controlled room temperature 20° to 25°C 
(68° to 77°F)Store at 20°C to 25°C (68°F-77°F) [see USP]. Please see package 
insert.  
 
15.24 Administration:  Dalteparin will be given 200 IU/kg/day subcutaneously.  The 
dosage will be calculated on the patient’s current weight in kilograms, rounded to 
the nearest whole kilogram.  The syringe dose will be chosen based on the weight 
adjusted calculation (see table 7.11).  .  The patient will be taught by on site 
nursing staff how to “waste” from each syringe such that the appropriate weight 
adjusted dose is delivered.  After the first month, dalteparin will be given 150 
IU/kg/day subcutaneously.  Dalteparin will be dispensed in one month supply 
aliquots to the patient.  Dalteparin will be stored according to the package insert.  
Patient instructions on proper subcutaneous injection techniques are included in 
appendix IX.   
 
 
15.25 Appearance:  Colorless solution in single-dose, prefilled syringes preassembled 
with a needle guard device. Each syringe contains 2,500, 5,000, 7,500, 10,000, 
12,500, 15,000 or 18,000 anti-Factor Xa international units (IU). 
 
 
15.26 Pharmacokinetic information:    
 
 
a)  Onset of action - Anti-Xa activity: Within 1-2 hours  
 
 
b)  Duration - >12 hours  
 
 
c)  Distribution - Vd: 40-60 mL/kg 
 
 
d)  Protein binding - Low affinity for plasma proteins  
 
 
e)  Bioavailability - SubQ: 81% to 93% 
 
 
f)  Half-life elimination (route dependent) - Anti-Xa activity: 2-5 hours; 
 
prolonged in chronic renal insufficiency: 3.7-7.7 hours (following a single 5000 
 
unit dose) 
 
 
g)  Time to peak, serum - Anti-Xa activity: ~4 hours 
 
 
h)  Excretion - Primarily renal  
 
 
15.27 Potential drug interactions: Dalteparin should be used with care in patients 
 
receiving oral anticoagulants, platelet inhibitors, and thrombolytic agents because 
 
of increased risk of bleeding.   
 
 
 
Please consult current drug reference sources for a complete list of potential drug 
 
interactions.  
 
 
15.28 Known potential toxicities:  As with all anticoagulants, bleeding is the major 
 
adverse effect of dalteparin.  Hemorrhage may occur at virtually any site. Risk is 
 
dependent on multiple variables.  Please consult the package insert for the most 
 
current and complete information. 
 
 
 
 
 
Adverse effects by frequency: 
 
 
 
>10%:  
 
Hematologic & oncologic: Hemorrhage (3% to 14%), thrombocytopenia 
(including heparin-induced thrombocytopenia, <1%; cancer clinical 


 
30  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
trials: ~11%) 
 
 
 
1% to 10%:  
 
 
 
Hematologic & oncologic: Major hemorrhage (≤6%), wound  
 
 
 
hematoma (3%) 
 
 
 
 
Hepatic: Increased serum ALT (>3 x ULN: 4% to 10%), increased serum 
 
 
AST (>3 x ULN: 5% to 9%) 
 
 
 
 
Local: Pain at injection site (≤12%), hematoma at injection site (≤7%) 
 
 
 
<1% (Limited to important or life-threatening):  
 
 
 
Alopecia, anaphylactoid reaction, gastrointestinal hemorrhage,   
 
 
hemoptysis, hypersensitivity reaction (fever, pruritus, rash, injections site 
 
 
reaction, bullous eruption), postoperative wound bleeding, skin necrosis,  
 
 
subdural hematoma, thrombosis (associated with heparin-induced  
 
 
thrombocytopenia). Spinal or epidural hematomas can occur following  
 
 
neuraxial anesthesia or spinal puncture, resulting in paralysis. 
 
15.29a Drug procurement:  Pfizer will supply the drug to Biologics, Inc.  Each 
participating ACCRU treating location will order the drug from Biologics, Inc.  
Fax the Drug Order Request Form (found in the forms packet) to: 
Biologics, Inc. 
Attn. Clinical Research Services 
Fax: 
 
 
Each participating ACCRU treating location will be responsible for monitoring 
the supply of dalteparin and will use the Drug Order Request Form to order 
additional supplies as needed. 
 
Outdated or remaining drug is to be destroyed on-site as per procedures in place 
at each institution. 
 
  
15.29b Nursing guidelines:    
• 
Instruct patients on self-injection technique.  
• 
Warn patient of increased risk of bleeding, including life threatening 
hemorrhage.  Patients should report excessive bruising and/or bleeding to the 
study team.  
• 
Monitor LFT’s and alert study team to changes in values. 
• 
Instruct patients that they need to notify their provider prior to any 
procedures, as their risk for bleeding is significantly increased. 
 
16.0  Statistical Considerations and Methodology  
 
16.1 
Sample Size Determination 
 
The primary objective of this study is to determine whether apixaban therapy has less 
major bleeding than low molecular weight heparin (dalteparin) in the treatment of 
patients with active cancer and confirmed acute deep-vein thrombosis (DVT) or 
pulmonary embolism (PE).  Important assumptions include a major bleeding rate of 6% 
over 6 months with clinically relevant non-major bleeding rates of 11-14% for those 


 
31  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
patients assigned to dalteparin.  The incidence of major bleeding ( or DVT) will be 
computed using the cumulative incidence funtion treating death without major 
bleeding ( or without DVT) as the competing risk. Rationale: to prevent potential 
bias in the comparison due to the difference in mortality rates between the two 
arms. Unstratified Cox models will be used in all analyses instead of stratified Cox 
models. Rationale: Based on data from previous studies which are used to design 
this trial, the incidence of major bleeding is extremely low. There will substantial 
loss of power with the use of stratified Cox models which the study was not powered 
for. Since this is a randomized study and the randomization is stratified by cancer 
stage and risk; we expect minimal confounding effect from these variables. This 
assumption is based on available published trial data summarized in the table:   
 
 
Author 
LMWH  
F/U (months) 
LMW VTE 
LMW Death 
LMW 
major 
bleed 
Lee (18) 
336 
6 
9% 
39% 
6% 
Kakkar (28) 
334 
12 
13.2% 
 
8.4% 
Hull (22) 
100 
12 
16% 
47% 
 
Monreal (29) 
203 
3 
9% 
 
5.4% 
Deitcher (21) 
122 
7 
6.6% 
 
 
 
 
The published rates of major and clinically relevant non-major bleeding for apixaban for 
VTE treatment (AMPLIFY trial) are 0.6% and 4.3% respectively. 
 
 
A superiority trial design is proposed.  Sample sizes, power estimates, and hazard ratios 
have been calculated with EAST 6.3 (Cytel Inc.). Patients will be randomized in a 1:1 
fashion.  Other assumptions used to determine the trial sample size include: 
• 
one sided significance = 0.05 
• 
power = 80% 
• 
6 month bleeding rate on control arm (dalteparin) = 6.0% 
• 
accrual rate: 10 patients per month 
• 
anticipated follow-up period: minimum of 6 months for each patient 
• 
assuming the 6 months major bleed rate in experimental 
 
arm (apixaban) is 1.4% and assuming major bleeding follows an exponential 
distribution, this corresponds to a hazard ratio (HR) of 0.22 
 
Based on the assumptions above, a sample size of 300 patients (150 per arm) would be 
required. We would accrue an additional maximum of 5% to account for ineligible 
patients and patients who withdraw from the study prior to receiving treatment. Hence the 
total maximum target accrual would be 315 (= 1.05 x 300) patients.  
The anticipated accrual period (assuming 10 patients per month) would be 30 months or 
approximately 2.5 years. It is anticipated that the primary analysis can take place after the 
last accrued patient was followed for 6 months or when 11 major bleeds have been 
observed. 
 
16.2 
Primary Hypothesis:  
 


 
32  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
We hypothesize that apixaban is associated with a significantly lower rate of major bleed 
compared to dalteparin in the treatment of patients with active cancer and confirmed 
acute deep-vein thrombosis (DVT) or pulmonary embolism (PE).  
 
There are two changes made to the analysis plan as of Amendment 3.  The original 
analysis plan was formulated by the previous study statistician. The following changes 
are proposed by the current study statistician for reasons explained below without 
knowledge of the outcome data.  The changes and rationale for those changes are 
summarized below. 
 
1. The incidence of major bleeding (or DVT) will be computed using the cumulative 
incidence function treating death without major bleeding (or without DVT) as the 
competing risk.  Rationale: to prevent potential bias in the comparison due to the 
difference in mortality rates between the two arms. 
 
2. Unstratified Cox models will be used in all analyses instead of stratified Cox models.  
Rationale: Based on data from previous studies which are used to design this trial, the 
incidence of major bleeding is extremely low.  There will be substantial loss of power 
with the use of stratified Cox models which the study was not powered for.  Since 
this is a randomized study and the randomization is stratified by cancer stage and 
risk, we expect minimal confounding effect from these variables. 
 
16.21 Primary Safety Analysis:  
 
All patients who received at least one dose of either apixaban or dalteparin 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 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. Patients who did not have a bleeding event during the predefined time 
of treatment and follow-up period, who were lost to follow-up, or who withdrew 
informed consent before the end of the predefined study duration and who did 
not have a bleeding event will be censored at the appropriate time.  The 
frequency of major bleeding events will be summarized separately by treatment 
arm.  The cumulative incidence of major bleeding at 6 months from treatment 
initiation and its associated 95% confidence interval will be estimated separately 
by treatment arm using a cumulative incidence function, treating death without 
bleeding as a cometing risk..   A Cox proportional hazard model will be used to 
determine the point estimate for the HR (comparing apixaban to dalteparin) and 
the p-value for the comparison between the two arms. If the one-sided p-value is 
less than 0.05, then apixaban will be declared to have a lower major bleeding rate 
in this population  
 
16.22 Secondary  Safety Analysis: 
 
A sensitivity analysis of the primary safety endpoint will be performed using the 
intent-to-treat population.  Cox’s proportional hazard model will be used to 
compare the major bleed events between the two. As before, a one-sided p-value 
will be used to determine whether apixaban has superior safety (i.e. smaller 
major bleed event rate than the control).  
  


 
33  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
The   secondary safety endpoint analysis will be on a treatment received basis. In 
this analysis, the composite endpoint of bleeding event defined as a major bleed 
or a clinically relevant non-major bleed will be used. For this analysis we will 
only include events that occurred during treatment or 7 days after treatment 
termination A similar analysis as described for the primary safety analysis will be 
used.  The impact of baseline covariates on the safety outcome will be Explored 
by adjusting for them in the Cox models. The frequencies of the separate 
components contributing to the safety outcome will be described. Other safety 
outcomes include all deaths and other vascular events. AEs will be coded using 
the MedDRA Dictionary.  Emergent adverse events will be defined as AEs 
occurring or worsening after randomization but not more than 7 days after study 
medication discontinuation. Events occurring during the 30 day follow up period 
will be described.  
 
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 methods described above for 
the primary endpoint. The impact of baseline covariates (location of DVT, renal 
clearance, age, sex, mobility at randomization, pulmonary disease, and cardiac 
disease) on the efficacy outcome will be explored adjusting for them in the Cox 
models.  Since this is a secondary endpoint, there is no adjustment for multiple 
comparisons.  This analysis will be conducted at the one-sided type I error of 
0.05.  
 
The assumption of proportional hazards will be checked for all Cox models 
(including primary and secondary endpointsand secondary analyese) using 
graphical methods aslog(-log)-plots and plots of scaled Schoenfeld residuals. 
 
16.3 
Handling of Missing Data: 
 
Monitoring and auditing procedures should be followed, in order to comply with 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. 
 
16.5 
Adeverse 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 


 
34  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
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  
  
18.0 
Records and Data Collection Procedures 
 
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 
   
 
18.1 Submission Timetable 
Initial Material(s)  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
  
On-Study  
 
≤2 weeks after registration 
Adverse Event - Baseline 
Selected  Concomitant Medication - Baseline   
End of Active Treatment/Cancel Notification  
Submit ≤2 weeks  after registration if withdrawal/refusal 
occurs prior to beginning protocol therapy 
Patient Questionnaire Booklet 
≤ 2 weeks after registration - Patient questionnaire booklet 
must be used; copies are not acceptable for this submission. 
Patient Questionnaire Booklet Compliance  
≤ 2 weeks after registration - This form must be completed 
only if the patient questionnaire booklet   contains absolutely 
NO patient provided assessment information. 
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 
  
 
Observation   
(3 months) 
Evaluation/Treatment Form (Arm A:  
Apixaban) (Cycle 1 Only) 
X 
  
 


 
35  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
CRF 
Active-Monitoring Phase 
(Compliance with Test Schedule Section 4.0) 
 
At each monthly 
evaluation during 
treatment 
At end of 
treatment 
  
 
Observation   
(3 months) 
Evaluation/Treatment Form (Arm A:  
Apixaban) 
X 
X 
 
Evaluation/Treatment Form (Arm B:  
Dalteparin)(Cycle 1 only) 
X 
  
 
Evaluation/Treatment Form (Arm B:  
Dalteparin) 
X 
X 
X 
Evaluation/Observation Form 
 
 
 X 
Recurrent Venous Thrombosis 
X 
X 
 X 
Adverse Event  
X 
X 
 X 
Non-CTCAE Bleeding Grading  
X 
 
 
Selected Concomitant Medication  
X 
X 
  
Laboratory 
X 
X 
 
Patient Questionnaire Booklet 
X1 
X 
  
  Booklet Compliance  
X2 
X 
  
Patient Compliance Questionnaire  
X 
X 
 
End of Active Treatment/Cancel Notification  
 
X 
 
Notification Form – Grade 4 or 5 Non-AER 
Reportable Events/Hospitalization  
At each occurrence 
(see Section 10.0) 
 
 
ADR/AER 
At each occurrence 
(see Section 10.0) 
 
 
1. Patient questionnaire booklet must be used; copies are not acceptable for this submission. 
2. This form must be completed only if the Patient Questionnaire booklet contains absolutely NO 
patient provided assessment information. 
 
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, will be supplied free of charge by 
Bristol Myers-Squibb.  The comparator drug, dalteparin, will be provided free of charge 
by Pfizer.   
 
 


 
36  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
References 
 
1. Prandoni, P., A. Piccioli, and A. Girolami, Cancer and venous thromboembolism: an overview. 
Haematologica, 1999. 84(5): p. 437-45. 
2. Nordstrom, M., et al., Deep venous thrombosis and occult malignancy: an epidemiological study. Bmj, 
1994. 308(6933): p. 891-4. 
3. Prandoni, P., et al., Deep-vein thrombosis and the incidence of subsequent symptomatic cancer. N 
Engl J Med, 1992. 327(16): p. 1128-33. 
4. Cormack, J., Phlegmasia alba dolens., in Trousseau A. Lectures on clinical medicine, delivered at the 
Hotel-dieu, Paris. 1872. p. 281-95. 
5. Heit, J.A., et al., Risk factors for deep vein thrombosis and pulmonary embolism: a population-based 
case-control study. Arch Intern Med, 2000. 160(6): p. 809-15. 
6. Heit, J.A., Risk factors for venous thromboembolism. Clin Chest Med, 2003. 24(1): p. 1-12. 
7. Khorana, A.A., et al., Thromboembolism is a leading cause of death in cancer patients receiving 
outpatient chemotherapy. J Thromb Haemost, 2007. 5(3): p. 632-4. 
8. Sorensen, H.T., et al., Prognosis of cancers associated with venous thromboembolism. N Engl J Med, 
2000. 343(25): p. 1846-50. 
9. Chew, H.K., et al., Incidence of venous thromboembolism and its effect on survival among patients 
with common cancers. Arch Intern Med, 2006. 166(4): p. 458-64. 
10. McBane RD, Wysokinski WE, Daniels PR, et al. Periprocedural anticoagulation management of 
patients with venous thromboembolism. Arterioscler Thromb Vasc Biol. 2010;30(3):442–448. 
11. Ashrani AA, Heit JA.  Risk factors for thrombosis in cancer patients. Cancer Treat Res. 2009;148:95–
114.  
12. Noble S, Pasi J. Epidemiology and pathophysiology of cancer-associated thrombosis. Br J Cancer. 
2010;102(suppl 1):S2–S9. 
13. Ashrani AA, Rajkumar SV. Chemotherapy-associated thrombosis. Cancer Treat Res. 2009;148:181–
206. 
14. Prandoni P, Trujillo-Santos J, Surico T, Dalla Valle F, Piccioli A, Monreal M; RIETE Investigators. 
Recurrent thromboembolism and major bleeding during oral anticoagulant therapy in patients with 
solid cancer: findings from the RIETE registry. Haematologica. 2008;93(9):1432–1434. 
15. Trujillo-Santos J, Nieto JA, Ruíz-Gamietea A, et al; RIETE Investigators. Bleeding complications 
associated with anticoagulant therapy in patients with cancer. Thromb Res. 2010;125(suppl 2):S58–
S61. 
16. Tafur AJ, Wysokinski WE, McBane RD, et al. Cancer effect on periprocedural thromboembolism and 
bleeding in anticoagulated patients. Ann Oncol. 2012;23(8):1998–2005. 
17. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, Nelson ME, Wells PS, 
Gould MK, Dentali F, Crowther M, Kahn SR. Antithrombotic therapy for VTE disease: 
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians 
Evidence-Based Clinical Practice Guidelines. Chest 2012;141:e419S-94S. 
18. Lee AYY, Levine MN, Baker RI et al. Low-Molecular-Weight Heparin versus a Coumarin for the 
Prevention of Recurrent Venous Thromboembolism in Patients with Cancer. N Engl J Med 
2003;349:146-153. 
19. Lee AY, Rickles FR, Julian JA, Gent M, Baker RI, Bowden C, Kakkar AK, Prins M, Levine MN.  
Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of 
patients with cancer and venous thromboembolism. J Clin Oncol. 2005;23:2123-9. 
20. Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, Le Maignan C, Extra JM, 
Cottu P, Farge D.  Comparison of low-molecular-weight heparin and warfarin for the secondary 
prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch 
Intern Med. 2002;162:1729-35. 
21. Deitcher SR, Kessler CM, Merli G, Rigas JR, Lyons RM, Fareed J; ONCENOX Investigators.  
Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin 


 
37  
 ACCRU# RU221501I 
BMS# CV185-444 
Amendment 3 
 
  
alone versus initial enoxaparin followed by warfarin for a 180-day period. Clin Appl Thromb Hemost. 
2006;12:389-96. 
22. 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. 
23. 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 Jul 1 (ahead of print). 
24. 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;368:699-708. 
25. Einstein Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 
2010;363:2499-510. 
26. Einstein PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N 
Engl J Med 2012;366:1287-97. 
27. Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a 
predictive model for chemotherapy-associated thrombosis. Blood. 2008;111:4902-7.  
28. Kakkar AK, Levine MN, Kadziola Z, Lemoine NR, Low V, Patel HK, Rustin G, Thomas M, Quigley 
M, Williamson RC.  Low molecular weight heparin, therapy with dalteparin, and survival in advanced 
cancer: the fragmin advanced malignancy outcome study (FAMOUS).  J Clin Oncol. 2004;22:1944-8. 
29. Monreal M, Falgá C, Valdés M, Suárez C, Gabriel F, Tolosa C, Montes J; Riete Investigators. Fatal 
pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism: findings 
from the RIETE registry. J Thromb Haemost. 2006;4:1950-6. 
30. Pocock SJ, Simon R.  Sequential Treatment Assignment with Balancing for Prognostic Factors in the 
Controlled Clinical Trial. Biometrics 31(1):103-115, 1975 Mar. 
 
31. Chee CE, Ashrani AA, Marks RS, Petterson TM, Bailey KR, Melton LJ 3rd, Heit JA.  Predictors of 
venous thromboembolism recurrence and bleeding among active cancer patients: a population-based 
cohort study.  Blood. 2014;123(25):3972-3978. 
 
32. Frost et al, Clinical Pharmacology: Advances and Applications 2014:6 179–187.