A Phase IV, Randomized, Double Blind Study Evaluating the Safety and Efficacy of Apixaban in Subjects With Calf Vein Thrombosis
Phase: PHASE4
Conditions: Deep Vein Thrombosis
Sponsor: Mayo Clinic

 
 
A Phase IV, Randomized, 
Double Blind Study Evaluating 
the Safety and Efficacy of 
Apixaban in Subjects with Calf 
Vein Thrombosis 
 
NCT03590743 
 
May 10, 2019 

 
 
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Robert D. McBane MD 
 
CONFIDENTIAL 
 
 
 
A Phase IV, Randomized, Double Blind Study Evaluating the Safety and 
Efficacy of Apixaban in Subjects with Calf Vein Thrombosis 
 
 
 
 
Regulatory Sponsor: 
 
 
 
 
 
Central Office:  
(Unblinding) 
 
Robert D. McBane MD 
Vascular Division, Department of Cardiology 
Gonda Vascular Center, Mayo Clinic  
Rochester MN 55905 
507-266-3964 
 
507-538-7178 / 507-255-2831 
 
Funding Sponsor: 
BMS/Pfizer via the ARISTA-USA program 
Study Product: 
Factor Xa Inhibitor (Apixaban) 
Protocol Number:  
(Mayo IRBe) 
17-009022 
 
 
BMS Protocol Number: 
CV185-678 
 
 
 
Initial version: 
27Feb2018 Version (1) 
Revised: 
 
31May2018 Version (2) 
Revised: 
 
10May2019 (3) 
 
 

 
 
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Robert D. McBane MD 
 
CONFIDENTIAL 
Table of Contents 
 
1 
INTRODUCTION .................................................................................................................................. 7 
1.1 
BACKGROUND ................................................................................................................................ 8 
1.2 
INVESTIGATIONAL AGENT .............................................................................................................. 11 
1.3 
CLINICAL DATA TO DATE............................................................................................................... 11 
1.4 
DOSE RATIONALE AND RISK/BENEFITS .......................................................................................... 12 
2 
STUDY OBJECTIVES ....................................................................................................................... 12 
3 
STUDY DESIGN ................................................................................................................................. 13 
3.1 
GENERAL DESIGN ........................................................................................................................ 13 
3.2 
PRIMARY STUDY ENDPOINTS ........................................................................................................ 14 
3.3 
SAFETY ENDPOINTS ..................................................................................................................... 15 
3.4 
SECONDARY ENDPOINTS .............................................................................................................. 15 
4 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL ........................................................ 16 
4.1 
INCLUSION CRITERIA .................................................................................................................... 16 
4.2 
EXCLUSION CRITERIA ................................................................................................................... 16 
4.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING ............................................................... 18 
4.3.1 
Recruitment of Patients ......................................................................................................... 18 
4.4 
EARLY WITHDRAWAL OF SUBJECTS............................................................................................... 18 
4.4.1 
Study Endpoint Achieved ...................................................................................................... 18 
4.4.2 
When and How to Withdraw Subjects ................................................................................... 20 
4.4.3 
Data Collection and Follow-up for Withdrawn Subjects ........................................................ 20 
5 
STUDY DRUG .................................................................................................................................... 20 
5.1 
DESCRIPTION ............................................................................................................................... 20 
5.2 
TREATMENT REGIMEN .................................................................................................................. 20 
5.3 
ULTRASOUND SURVEILLANCE ........................................................................................................ 20 
5.4 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ....................................................... 21 
5.4.1 
Stratification ........................................................................................................................... 21 
5.4.2 
Central Automated Randomization ....................................................................................... 21 
5.5 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ................................................................... 21 
5.6 
PRIOR AND CONCOMITANT THERAPY ............................................................................................. 23 
5.7 
PACKAGING ................................................................................................................................. 23 
5.8 
BLINDING OF STUDY ..................................................................................................................... 23 
5.8.1 
Receipt of Drug Supplies ....................................................................................................... 23 
5.8.2 
Storage .................................................................................................................................. 23 
5.8.3 
Dispensing of Study Drug ...................................................................................................... 23 
5.8.4 
Return or Destruction of Study Drug ..................................................................................... 24 
6 
STUDY PROCEDURES ..................................................................................................................... 24 
6.1 
VISIT 1 (DAY 0) ............................................................................................................................ 24 
6.2 
SURVEILLANCE AND FOLLOW UP. .................................................................................................. 24 
7 
STATISTICAL CONSIDERATIONS .................................................................................................. 26 
7.1 
SAMPLE SIZE DETERMINATION ...................................................................................................... 26 
7.2 
STATISTICAL METHODS ................................................................................................................ 27 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ....................................................................................... 28 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................... 29 
8.1 
DEFINITIONS ................................................................................................................................ 29 
LABORATORY TEST ABNORMALITIES .......................................................................................................... 32 
8.2 
RECORDING OF ADVERSE EVENTS ................................................................................................ 33 

 
 
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Robert D. McBane MD 
 
CONFIDENTIAL 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................. 33 
8.3.1 
Sponsor-Investigator reporting: notifying the Mayo IRB ....................................................... 33 
8.3.2 
Sponsor-Investigator reporting: Notifying the FDA................................................................ 34 
8.4 
MEDICAL MONITORING ................................................................................................................. 34 
9 
DATA HANDLING AND RECORD KEEPING ................................................................................... 35 
9.1 
CONFIDENTIALITY ......................................................................................................................... 35 
9.2 
SOURCE DOCUMENTS .................................................................................................................. 35 
9.3 
CASE REPORT FORMS.................................................................................................................. 35 
9.4 
RECORDS RETENTION .................................................................................................................. 36 
10 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................................. 36 
10.1 
STUDY MONITORING PLAN ............................................................................................................ 36 
10.2 
AUDITING AND INSPECTING ........................................................................................................... 36 
11 
ETHICAL CONSIDERATIONS .......................................................................................................... 37 
12 
STUDY FINANCES ............................................................................................................................ 37 
12.1 
FUNDING SOURCE ........................................................................................................................ 37 
13 
PUBLICATION PLAN ........................................................................................................................ 37 
14 
REFERENCES ................................................................................................................................... 37 
 
 
 
 
 
 
 
 

 
 
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Robert D. McBane MD 
 
CONFIDENTIAL 
 
List of Abbreviations 
 
AE 
Adverse Event/Adverse Experience 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
 
 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
 
cDVT 
Calf deep vein thrombosis 
 
 
 

 
 
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Robert D. McBane MD 
 
CONFIDENTIAL 
Study Summary 
Title 
A Phase IV, Randomized, Double Blind Placebo 
controlled Study Evaluating the Safety and Efficacy of 
Apixaban in Subjects with Isolated Calf Vein 
Thrombosis 
Running Title 
Golden Calf Trial 
Protocol Number 
17-009022 
Phase 
Phase IV 
Methodology 
Single center, multi-Mayo site randomized, double blind, 
placebo-controlled, superiority clinical trial. 
Overall Study 
Duration 
36 months 
Subject Participation 
Duration 
Each individual will be in the study for 3 months  
Single or Multi-Site  
Single center, multi-Mayo site Trial  
Objectives 
There are two primary objectives.  The first primary objective is 
to evaluate whether a strategy of active anticoagulation with 
apixaban is more efficacious than no anticoagulation (i.e., 
placebo) when monitored with serial ultrasound imaging in the 
management of patients with isolated calf vein thrombosis 
(DVT) for the composite endpoint consisting of prevention of 
thrombus propagation, pulmonary embolism, recurrent venous 
thromboembolic events, and all cause mortality.  The second 
primary objective, safety, is to assess the combination of major 
and clinically relevant non-major bleeding for subjects 
randomized to apixaban vs. placebo control.   
Number of Subjects 
The number of patients needed is 250, or 125 in each of the 
two treatment arms. 
Diagnosis and Main 
Inclusion Criteria 
Patients will be recruited for study participation if they have a 
newly diagnosed venous thrombotic event (DVT) limited to the 
calf veins.   
Study Product, 
Dose, Route, 
Regimen 
Apixaban (10 mg twice daily for 7 days followed by 5 mg twice 
daily for 3 months) or matching placebo. 
Duration of 
Administration 
Total duration of drug administration will be for the duration of 
study participation 3 months. 
Reference therapy 
Serial clinical monitoring as is standard of practice with 
matching placebo.  All patients will undergo serial ultrasound 
imaging at day 7, day 14, and day 90.   
 Primary Endpoint 
Combined endpoint including thrombus propagation, pulmonary 
embolism, recurrent venous thromboembolism, and all cause 
mortality over three months. 

 
 
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Robert D. McBane MD 
 
CONFIDENTIAL 
Sample Size 
Estimation 
An anticipated venous thromboembolic event rate of 10.0 to 
12.6% within 3 months for patients randomized to standard 
medical observation and placebo is expected. We hypothesize 
the apixaban arm will result in a 3 month event rate of 1.0% to 
2.3%. At an interim-analysis alpha level of 0.049 and events 
rates of 10% and 1.6% for placebo and apixaban, respectively, 
a sample size of 121/gp is required to achieve 80% power. To 
account for minor attrition over the course of the study, 125/gp 
or 250 total is planned for target enrollment.   
Statistical 
Methodology 
The primary outcome measure will be tested using a Cochran-
Mantel-Haenszel chi-square with clinical site considered as a 
stratification variable. The pooled estimate of the odds ratio will 
be used as the primary measure of effect. The study is 
designed with an interim analysis with an information fraction of 
40%. The O’Brien-Fleming alpha spending function will be used 
to provide control over the type I error rate.  
 
 
 

 
 
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Robert D. McBane MD 
 
CONFIDENTIAL 
1 Introduction 
This document is a protocol for a human research study. This study will be 
carried out in accordance with the applicable United States government regulations and 
Mayo Clinic research policies and procedures.    
Each year, between 300,000 to 600,000 individuals suffer an acute venous 
thromboembolic event (1-4).  These events primarily involve the deep veins of the lower 
extremities (deep vein thrombosis, DVT) which may lead to embolization to the 
pulmonary arteries (pulmonary embolism, PE).  Deep vein thrombosis of the lower 
extremity is divided into two categories depending on the proximal extent of thrombosis.  
Thrombi involving the popliteal, femoral and iliac veins are categorized together into 
“proximal DVT” largely due to their increased embolic potential.  Indeed, the risk of 
embolization of proximal DVTs may be as high as 50% (3).  Whereas the risk of 
mortality associated with a PE is high, prompt identification and treatment initiation with 
anticoagulants is a medical emergency.  Both the evaluation and management of 
proximal DVT and PE has been well established by randomized controlled trial data (5).   
In contrast, the management of venous thrombi limited to the calf veins is not 
well established (6).  “Distal” deep vein thrombosis involve either the deep (posterior 
tibial, peroneal calf, and anterior tibial) or muscular (soleal and gastrocnemius) veins of 
the calf but do not extend into the popliteal veins.  These “calf vein thrombi” (cDVT) are 
numerous and account for half of the DVT burden in a community setting (150,000 – 
300,000 events annually in the United States) (7).  While the likelihood of embolization 
is low, propagation of calf vein thrombi to the popliteal vein greatly augments the PE 
risk.  Prevention of thrombus propagation can be readily accomplished with 
anticoagulation therapy however this therapy comes with a small risk of major 
hemorrhage (8).  As such, management strategies vary considerably across sites with 
some investigators advocating conservative ultrasound surveillance without 
anticoagulation while others recommend full anticoagulant therapy for three months.  
There are few adequately powered randomized controlled trial data to guide 
management of these patients.  The guidelines recommend serial ultrasound imaging 
for 2 weeks over anticoagulation therapy unless symptoms are severe or there are risk 
factors for thrombus extension (5).  These guidelines are problematic for several 
reasons.  First, the weight of the recommendation is based on expert opinion only 
(Grade 2C) and second, validated risk prediction tools for thrombus propagation do not 
exist (9).  Current guidelines also suggest anticoagulation if the thrombus extends but 
remains confined to the distal veins (Grade 2C).  There are little data to support this 
latter recommendation.  Recently, the FDA has approved an oral direct factor Xa 
inhibitor, apixaban, which has been shown to be a highly effective anticoagulant for VTE 
(10).  This agent has a particular advantage in that it is associated with very low 
bleeding rates making this anticoagulant particularly attractive for the treatment of 
cDVT.  
We propose a phase IV, randomized, double blind placebo controlled study 
evaluating the safety and efficacy of apixaban compared to observation with serial 
ultrasound imaging alone in subjects with acute venous thrombosis limited to the calf 
veins.  The primary objective is to evaluate whether a strategy of anticoagulation with 
apixaban is more effective than serial ultrasound imaging in the management of patients 

 
 
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Robert D. McBane MD 
 
CONFIDENTIAL 
with cDVT for the prevention of thrombus propagation, pulmonary embolism and 
recurrent venous thromboembolic events. 
1.1 Background 
Venous thromboembolism (VTE) represents a major cause of morbidity and 
mortality in the USA.(1–3) The incidence of VTE exceeds 1 per 1000 with as many as  
600,000 first life-time cases diagnosed annually in this country. The 7 day mortality of 
patients suffering a thrombotic event is 25% and up to 35% of patients with pulmonary 
embolism (PE) die suddenly. Venous thromboembolism is therefore the fourth leading 
cause of death in Western society and the third leading cause of cardiovascular death 
behind myocardial infarction and stroke. Furthermore, VTE is both a recurrent disease 
and a morbid disease. Of those individuals surviving the thrombotic event, 30% will 
develop recurrent venous thromboembolism within 10 years and 20–30% will develop 
the post-phlebitic syndrome over this time period. VTE is typically a disease of elderly 
people, with the incidence of thrombotic events increasing significantly beyond age 60. 
As our population ages, the expected number of VTE annually will increase. Despite 
advances in radiographic detection, expanded knowledge of risk factors, and 
anticoagulant development, the incidence of VTE has been relatively constant over the 
past several decades. 
Isolated cDVT accounts for nearly half of all DVTs occurring the United States 
each year (7).   As such, as many as 300,000 cases annually require thoughtful 
management (1,7).  And yet, there is very little high quality data to guide clinicians 
managing these patients.  Indeed, the precise incidence of cDVT in the community is 
not well established.  It is felt that the embolic potential of cDVT left untreated is low and 
embolization risk only increases with thrombus propagation to the popliteal vein or 
higher.  The risk of proximal propagation if untreated ranges from 2 to 23% and likely 
varies by the clinical context (6).  Cancer, recent surgery, hospital confinement, prior 
history of VTE and large thrombus size are said to be risk factors for thrombus 
propagation (5).  These factors are derived from different cohorts and do not necessarily 
deserve the same weighting in a risk assessment strategy.  A dedicated risk 
stratification tool would be immensely helpful to identify those individuals most likely to 
benefit from anticoagulation therapy however such a tool does not exist.   
The RIETE VTE registry identified 1,921 patients with cDVT and compared the 
risk factors and natural history to 9,165 patients with proximal DVT (16).  Of this cohort, 
89% received anticoagulant therapy for at least 3 months.  Patients with cDVT were 
significantly younger (65 vs. 70 years), more likely to occur in an inpatient setting (35% 
vs. 28%), more frequently post-operative (15% vs. 11%), more likely to occur following 
prolonged travel > 6 hours (3.4% vs. 1.9%) or in the setting of varicose veins (25.7% vs. 
20.3%). In contrast, active cancer, pregnancy, and a prior history of VTE were 
significantly more common in patients with proximal DVT.  At 3 months, VTE recurrence 
rates were similar for cDVT receiving anticoagulation compared to proximal DVT (2.0% 
vs. 2.7%, P = 0.07).  Major bleeding (1.0% vs. 2.2%, P < 0.01), and mortality rates 
(2.7% vs. 7.5%; P < 0.001) were lower for cDVT patients.  Furthermore, these 
investigators found that patients with isolated cDVT are more often associated with 
transient or reversible risk factors compared to proximal DVT.   

 
 
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Robert D. McBane MD 
 
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CALTHRO was a natural history study to assess the hypothesis that it is safe to 
withhold anticoagulation in patients with cDVT (17).  A total of 65 patients had cDVT 
managed without anticoagulants.  For these patients, the 3 month event rate was 7.8% 
including PE, proximal DVT and recurrent cDVT.  In summary, isolated cDVT may not 
be as benign as the guidelines would suggest particularly from the perspective of VTE 
recurrence (5). 
Managing cDVT is therefore particularly challenging for a number of reasons.  
First, there are few community based epidemiology cohort studies to assess risk factors 
for cDVT.  Second, there is a dearth of information regarding the natural history of this 
disease.  Many studies combine deep veins and muscular veins together under the 
same category yet these veins are not anatomically similar and likely carry very different 
embolic and thrombotic propagation  propensity.  Third, there is a paucity of strong 
clinical trial data to help guide treatment decisions.  Many of the prominent clinical trials 
excluded cDVT as an entry event.  Disparity exists across institutions regarding 
management protocols.  Indeed, many institutions don’t mandate calf vein imaging as 
part of their ultrasound protocol.  It is the practice in some clinicians to provide full 
anticoagulant therapy for patients with cDVT for three months.  Other clinicians pursue 
serial imaging over 2 to 3 weeks and only provide anticoagulant therapy if there is 
evidence of thrombus propagation to the popliteal vein, embolization to the pulmonary 
vasculature or symptomatic recurrent venous thrombosis in other locations.  Both 
camps would point to small studies to support their approach.  The most appropriate 
strategy however remains unclear given the lack of strong data. 
There have been 6 treatment trials of isolated cDVT (7,11-15).  Trial sizes ranged 
from 32 to 259 patients with a total randomized in all six trials combined of 711 subjects 
(Table 1).  Treatment varied from serial observation to full anticoagulation with warfarin.  
Treatment duration varied from 10 days to 3 months.   
The CACTUS trial is the largest and most recent randomized trial to address this 
question (15).  This was a multinational European trial with 23 participating centers from 
3 countries.  In this trial, 259 subjects with isolated cDVT were randomized to receive 
either subcutaneous Nadroparin 171 IU/kg/day or placebo for 42 days.  The primary 
endpoints of the trial included cDVT extension, proximal DVT or PE.  The primary safety 
endpoints were a combination of major plus clinically relevant non-major bleeding.  
Study endpoints were assessed at 42 and 90 days from enrollment.  Venous thrombosis 
extension was assessed by compression ultrasonography at 3 – 7 days and at 42 days.  
At 90 days, subjects were contacted by telephone follow up.  There was no difference in 
the primary efficacy outcome at 42 days (3% vs. 5%).  At 90 days, the composite 
outcome was 3.3% in patients receiving LMWH compared to 6.6% for matching placebo 
(absolute risk difference -2.9%; 95% CI -8.7% to 2.8%; p value 0.28).  There were 4% 
bleeding outcomes in subjects receiving LMWH however only one bleeding event was 
deemed a major bleed (0.8%).  The investigators concluded that LMWH treatment for 
42 days was not superior to placebo and resulted in excessive bleeding.  There are a 
number of difficulties with this study which deserve notation (9).  First, the slow 
enrollment of this trial implies strong selection bias.  With 22 centers enrolling over 6 
years, each center would have enrolled less than 2 patients per year.  These 
investigators met only half of their anticipated enrollment of 572 subjects thus 
substantially reducing their power for identifying a difference between study arms.  

 
 
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Robert D. McBane MD 
 
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Second, the exclusion criteria were likely too extreme.  Patients were excluded from 
participating if they had a prior history of VTE, cancer, thrombocytopenia, chronic kidney 
disease, obesity/low body weight or NSAID use.  Third, the safety endpoint included 
major bleeding plus clinically relevant non-major bleeding.  The investigators concluded 
that the bleeding rate of 4% offset any benefits of thrombotic risk reduction however the 
safety outcome included only 1 patient with major bleeding (0.8%) which is a low and 
very acceptable rate for VTE treatment.  If you compare the bleeding rate of 0.8% to the 
thrombotic rate of 6.6%, this would seem to be a reasonable tradeoff.  In summary, the 
CACTUS trial provides important data however does not convincingly answer this 
question.   
A trial by Schwarz et al. assessed consecutive patients with symptomatic cDVT 
limited to the muscular venous segments (soleal or gastrocnemius veins). (14)  
Exclusion criteria included peroneal or posterior tibial DVT, PE, prior cDVT, heparin 
induced thrombocytopenia, chronic kidney disease or active bleeding.  These 
investigators assigned 109 patients to receive either Nadroparin 180 IU/kg/day for 10 
days with compression hose or compression hose alone.  The primary study endpoint 
was either thrombus propagation assessed by compression ultrasonography (day 3, 
day 10-12, 4 weeks and 3 months) or symptomatic PE.  Two patients in each group 
were found to have thrombus propagation (3.78%).  There were no PEs, major bleeds 
or deaths in either group.  While helpful, these data have major limitations largely 
related to subject recruitment including low rate of active cancer (4.7%), exclusion of 
patients with posterior tibial or peroneal DVT, patient immobility (22%), and 
hospitalization (10.7%) thus limiting the applicability to real world clinical practice.  
The ACT trial was a well done pilot, single-center study largely performed to 
establish study feasibility (7).  From 2011 to 2012, these investigators enrolled 70 
consecutive patients with calf DVT to receive either LMWH/warfarin or 
NSAID/paracetamol for 3 months. The primary endpoint of this study was thrombus 
propagation and PE.  Ultrasound was performed at 7 days and 21 days with telephone 
follow up at 3 months. There were no thrombotic events for subjects randomized to 
LMWH/warfarin.  For subjects randomized to NSAID/paracetamol, the composite event 
rate was 11.4% including 2.9% rate of PE.  Due to small trial size, these differences did 
not reach statistical significance (p=0.11).  There were no major bleeding events.  The 
time in therapeutic range for those randomized to active treatment was 56%.  While no 
firm conclusions can be drawn from this small study, the data is very useful for accrual 
calculations for a properly powered study.  Furthermore, this study establishes feasibility 
for study recruitment in such a study in contrast to the slowly enrolling CACTUS trial.   
Based on these treatment trials, guideline recommendations for patients with 
cDVT include a preference for serial ultrasound evaluation with observation over 
anticoagulation therapy in the absence of severe symptoms, active cancer, hospitalized 
status, prior history of VTE, unprovoked event, multiple venous involvement or large 
thrombus size (> 7 mm width and or > 5 cm length) or positive fibrin D-Dimer (5).    This 
approach however has several disadvantages.  First, if untreated patients 
participating in the randomized trials and cohort studies are combined, the anticipated 
event rate for untreated VTE is relatively high at 11.2% at 3 months (7,12,14,15,17).  
This includes a DVT propagation rate of 4.8%, PE rate of 1% and VTE recurrence rate 
of 5.4%.  These event rates are high by comparison to patients with unprovoked 

 
 
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Robert D. McBane MD 
 
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proximal DVT or PE.  For unprovoked proximal DVT or PE, the event recurrence rate is 
approximately 8% at one year and 30% at 5 years.  For these unprovoked VTE, there is 
universal agreement that continued anticoagulation therapy is indicated (Grade 1A) (5).  
If the latter deserves ongoing anticoagulant therapy then cDVT should deserve 
consideration for anticoagulant therapy as well.  Second, the reason for avoiding 
anticoagulant therapy is said to be due to increased rate of major bleeding.  In the 
CACTUS trial, this rate was acceptably low at 0.8% (15).  In the trial by Ferarra et al, 
there were no major bleeding events despite enrollment confined to post-operative 
patients (13).  Third, the post thrombotic syndrome following cDVT is said to be low 
however this has not been adequately studied and no firm conclusion can yet be 
established.  Fourth, cDVT was specifically excluded from the recent large randomized 
trials of DOACs.  Fifth, serial ultrasound does nothing for VTE prevention.  Timing the 
interval to 7 days between studies may place the patient at considerable risk of 
thrombotic propagation and embolization which may prove to be a life threatening 
event.  For these combined reasons, a prospective randomized trial of anticoagulant 
therapy compared to serial ultrasound imaging strategy is necessary and important.  
Given the vast number of patients suffering calf DVT each year in our society, 
establishing the most appropriate treatment strategy is paramount. 
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%, for doses up to 10 mg, after oral dosing with maximum concentrations at 4 hours 
post ingestion.  The pharmacokinetics are linear and plasma protein binding in humans 
is high at nearly 90% with a volume of distribution of approximately 20 liters.  Apixaban 
is metabolized in the liver mainly via CYP3A4 pathway.  Renal excretion accounts for 
about 27% of total clearance.  Approximately 25% of the drug is eliminated in the feces. 
This drug is not dialyzable due to its high plasma protein binding (the systemic exposure 
of apixaban is 14% lower for patients on dialysis when compared to not on dialysis).  
Apixaban is currently FDA approved to reduce the risk of stroke and systemic embolism 
in patients with nonvalvular atrial fibrillation, for the treatment of DVT and PE, and for 
the reduction in the risk of recurrent DVT and PE following initial therapy and 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. 
1.3 Clinical Data to Date 
The AMPLIFY investigators randomized 5,395 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 (10).  From an efficacy standpoint, apixaban was 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-Ext investigators randomized 2486 patients with VTE 
who had recently completed 6 – 12 months of anticoagulation to receive one of two 

 
 
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Robert D. McBane MD 
 
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doses of apixaban or placebo for an additional 12 months.  Both apixaban doses 
reduced recurrent VTE without increasing major bleeding compared to placebo (18).    
Apixaban is a contender for first line therapy for cDVT for several reasons. First, 
the twice daily dosing of apixaban, although less convenient, may improve efficacy and 
safety.  The peak levels are anticipated to be lower than once daily dosing thus 
decreasing potential bleeding.  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 patients who may 
have mild renal or hepatic impairment.  Third, apixaban has been shown to have 
extremely low rates of major bleeding.   In patients with cDVT, the risk reduction of VTE 
propagation, embolization, or recurrence will more than offset the low bleeding rate.   
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 (10).  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 non-inferiority (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-Ext investigators compared continued apixaban 
(2.5 mg or 5 mg, twice daily) with placebo in 2486 patients who had just completed 6 – 
12 months of treatment for an acute VTE (18).  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 dosing prescribed.   
2 Study Objectives 
Primary Objective:  There are two primary objectives.  First, the primary efficacy 
outcome is to evaluate whether a strategy of active anticoagulation with apixaban is 
more effective than serial ultrasound imaging in the management of patients with 
isolated calf vein thrombosis (cDVT) for the prevention of the composite outcome 
including thrombus propagation, pulmonary embolism, recurrent venous 
thromboembolic events, and all-cause mortality.   
 
Second, the principal safety outcome is to assess the combination of major and 
clinically relevant non-major bleeding for subjects randomized to apixaban vs. placebo 
control.   
 
Secondary Objective:  There will be two secondary objectives.   
 
The first is to assess the timing of thrombus propagation.  The current understanding of 
thrombus propagation is that if it occurs, it will occur within the first 2 weeks of 

 
 
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diagnosis.  This concept of timing of thrombus propagation is the basis for current 
guideline endorsed approach which limits the requirement for repeated ultrasound up to 
2 weeks only.  Yet, this guideline recommendation has not been validated.  Our study is 
poised to verify this assumption.    
 
The second is to determine net clinical benefit or harm for the two strategies.  The 
outcome of net clinical benefit or harm will be assessed as the composite of the primary 
efficacy outcome or the principal safety outcome up to day 90. 
3 Study Design 
3.1 General Design 
This is a Single center, multi-Mayo site, randomized, double-blind, placebo-
controlled, superiority clinical trial.  Major bleeding and clinically relevant non-major 
bleeding will also be evaluated.  Subjects will be screened at both outpatient clinic visit 
appointments or during hospitalization using direct referrals or by daily automated 
electronic screening of vascular radiology ultrasound and computed tomography 
reports.  The baseline ultrasound will be clinical indicated, obtained for this purpose, 
and will be carefully reviewed by study personnel.  Interested qualified subjects will be 
consented and offered participation in this trial.  Pre-randomization anticoagulation 
treatment for cDVT is allowed up to a maximum of 72 hours.  After randomization, 
patients allocated to apixaban will receive 10 mg twice daily for 7 days, followed by 5 
mg twice daily for 3 months. Patients allocated to placebo control will receive twice daily 
matching placebo tablets in a similar fashion.  All patients will undergo serial ultrasound 
imaging at 7 days, 14 days and 90 days.  Patients developing symptomatic DVT or PE 
will be evaluated by cross-sectional imaging (ultrasound or computed tomography 
(CTA)) appropriate for their symptom assessment as part of their standard care.  
Allocation to treatment will be done centrally.  Once consent has been obtained, 
clinically indicated baseline laboratory values will be confirmed (drawn within past 4 
weeks) and subjects will begin treatment and follow-up for 3 months.   
The primary composite efficacy endpoint of this study will be a composite of 
thrombus propagation, pulmonary embolism (PE), symptomatic VTE recurrence 
including recurrent DVT, PE or all cause fatality.  The primary safety outcome will be 
major bleeding and clinically relevant non-major bleeding (ISTH criteria; 21). All 
suspected recurrent VTE, deaths, as well as all episodes of bleeding and vascular 
events will be evaluated by a central, blinded, independent adjudication committee. 
Adjudication results will be the basis for the final analyses.  
There will be two secondary endpoints.  The first will assess the timing of 
thrombus propagation relative to the original date of diagnosis for those individuals who 
experience a thrombus propagation.  The second will be an assessment of net clinical 
benefit or harm assessed as the composite of the primary efficacy outcome or the 
principal safety outcome up to day 90. 
 
 
 
 
 

 
 
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3.2 Primary Study Endpoints 
The primary composite efficacy endpoint of this study will include thrombus 
propagation either within the calf veins or into proximal deep veins (popliteal, femoral or 
iliac veins), symptomatic or incidental VTE recurrence or all-cause mortality by day 90.  
The following criteria will be used to confirm and categorize an outcome VTE event:  
1. Thrombus propagation:  The original calf DVT must be confirmed by either 
duplex ultrasonography, venography, CT, or MRI.  All patients will then undergo 
serial ultrasound imaging at 7 days, 14 days and 90 days.  Propagation is 
defined by two criteria: (1) when a thrombus previously confined to the calf veins 
is found to extend into a proximal vein including popliteal, femoral or iliac veins of 
the ipsilateral limb or (2) if the thrombus extends but remains confined to the calf 
veins. The thrombus propagation must be confirmed by comparing the new 
imaging with previous imaging clearly showing extension into a proximal vein not 
seen on the original imaging study.  Thrombus propagation that remains confined 
to the calf veins must extend beyond 5 cm of the previous thrombus length, 
extend into a new venous segment (upper, mid, or lower), or involve a new vein 
(not previously involved) within the calf (example, the original involvement was 

 
 
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confined to the posterior tibial vein and now there is new involvement of the 
gastrocnemius vein.)     
2. Recurrent DVT:  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.    
3. PE: Symptomatic pulmonary emboli must be confirmed by either CT, MR or 
conventional pulmonary angiography or VQ perfusion imaging.     
4. Incidental VTE recurrence:  It is anticipated that recurrent venous thrombosis or 
thrombus propagation may be identified incidentally (without new or changing 
symptoms).  In order to be classified as an event, the thrombus in question must 
be confirmed by cross sectional imaging (duplex ultrasonography, venography, 
CT, MRI or VQ). 
5. All-cause mortality   
3.3 Safety Endpoints 
The primary safety endpoints will include the major bleeding and clinically 
relevant non-major bleeding.  This will include any episode of major bleeding including 
fatal bleeding or any episode of clinically relevant non-major bleeding.  The following 
criteria will be used to confirm and categorize a bleeding episode: 
1. Major bleeding: 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 
bleeding at a critical site: intracranial, intraspinal, intraocular, retroperitoneal, 
pericardial intra-articular, intramuscular with compartment syndrome, or fatal 
bleeding. 
2. Clinically relevant non-major bleeding: Clinically relevant non-major bleeding 
is defined as any overt, actionable sign of hemorrhage meeting at least one of 
the following criteria: (i) requiring nonsurgical, medical intervention by a 
healthcare professional, (ii) leading to hospitalization or increased level of care, 
or (iii) prompting evaluation. 
3. Minor bleeding: Minor bleeding is defined as overt bleeding that did not meet 
criteria for major bleeding. 
All suspected recurrent VTE, deaths, as well as all episodes of bleeding and 
vascular events will be evaluated by a central, blinded, independent adjudication 
committee. Adjudication results will be the basis for the final analyses.  
3.4 Secondary Endpoints 
The first secondary endpoint will be to establish the timing of thrombus 
propagation for those individuals who have suffered such an event.  The date of 
thrombus propagation confirmation will be compared to the date of the original DVT 
diagnosis for this purpose.    

 
 
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The second secondary outcome will include an assessment of net clinical benefit 
or harm as the composite of the primary efficacy outcome or the principal safety 
outcome up to day 90. 
 
4 Subject Selection Enrollment and Withdrawal 
4.1 Inclusion Criteria 
1. Age range: ≥ 18 years 
2. Both males and females 
3. Confirmed acute calf vein thrombosis confined to either the deep (posterior tibial, 
anterior tibial, or peroneal) or muscular (gastrocnemius or soleal) veins. 
4. Negative serum or urine pregnancy test done (within 2 weeks) 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. 
5. Ability to provide written informed consent. 
4.2 Exclusion Criteria 
1. 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 
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. 
 
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. 
 
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 

 
 
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methods of contraception. Highly effective methods of contraception have a 
failure rate of < 1% when used consistently and correctly. 
 
At a minimum, subjects must agree to the use of one method of highly effective 
contraception as listed below: 
 
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION 
• Male condoms with spermicide 
• Hormonal methods of contraception including combined oral contraceptive 
pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) such 
as Mirena® by WOCBP subject or male subject’s WOCBP partner. 
• Female partners of male subjects participating in the study may use hormone 
based contraceptives as one of the acceptable methods of contraception 
since they will not be receiving study drug,  
• IUDs such as ParaGard®,  
• Tubal ligation  
• Vasectomy. 
• Complete Abstinence* 
*Complete abstinence is defined as complete avoidance of heterosexual 
intercourse and is an acceptable form of contraception for all study drugs. 
Acceptable alternate methods of highly effective contraception must be 
discussed in the event that the subject chooses to forego complete abstinence 
2. Acute co-existing proximal DVT (popliteal, femoral, iliac veins or IVC), pulmonary 
embolism, splanchnic vein thrombosis, cerebral venous sinus thrombosis within 
the past 3 months for whom anticoagulation therapy is indicated. 
3. Age < 18 years. 
4. Continuous treatment with therapeutic anticoagulant for more than 72 hours pre-
randomization. 
5. Contraindication to anticoagulant therapy 
6. Significant kidney disease. Creatinine clearance < 25 ml/min using the Cockcroft-
Gault equation:  GFR = (140-age) * (Wt in kg) * (0.85 if female) / (72 * Cr). (within 
last four weeks) 
7. Significant liver disease (e.g. acute hepatitis, chronic active hepatitis, cirrhosis) or 
ALT (or AST) > 3 x ULN. (within last four weeks) 
8. Platelet count < 50 x109/L.(within last four weeks) 
9. Life expectancy < 12 months. 
10. Current active bleeding. 
11. Concomitant use of strong CYP3A4 inhibitors (e.g., HIV protease inhibitors, 
systemic ketoconazole) or strong CYP 3A4 inducers like rifampicin. 
12. Active cancer defined as any evidence of cancer on cross-sectional imaging or 
cancer treatments within the past 6 months (chemotherapy, radiation therapy or 
cancer related surgery).   
13.  Anticipated need for urgent/emergent surgery or major invasive procedure.   

 
 
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14. Dual antiplatelet therapy (thienopyridine plus aspirin) and/or aspirin greater than 
165 mg while on study medication. 
4.3 Subject Recruitment, Enrollment and Screening 
This is a multi-Mayo center, randomized, double blind, placebo controlled, 
superiority trial for efficacy.  Experienced data management personnel enroll patients, 
collect clinical trial data and ensure quality control.  Patient registration occurs using 
centralized registration and randomization systems to ensure patient eligibility.  The 
Research Radiology Core provides radiological image management including a 
centralized system of image collection, archiving and review for clinical studies.  The 
Research Pharmacy Core offers a central pharmacy service, along with quality-control 
systems for medication order fulfillment, shipment and reconciliation. 
Patients will be recruited from two potential sources, hospital in-patients and out-
patients attending anticoagulation clinics at one of three sites: Mayo Clinic Rochester, 
Mayo Clinic Eau Claire, or Mayo Clinic La Crosse.  Upon subject identification, the study 
will be explained in detail by the investigators or study coordinator, the consent form 
reviewed, questions answered, and the consent form signed.   
4.3.1 Recruitment of Patients   
We anticipate that a sizable percentage of patients will be recruited from Mayo 
Clinic Rochester.  Patients will be recruited from Mayo Clinic Rochester, Mayo Clinic 
Eau Claire, or Mayo Clinic La Crosse.   
4.4 Early Withdrawal of Subjects 
4.4.1 Study Endpoint Achieved 
A small percentage of patients will meet either a thrombotic or bleeding outcome 
event as part of trial participation.  These outcomes may be clinically symptomatic or 
may be identified as part of either the serial ultrasound imaging protocol or cross-
sectional imaging obtained for other clinically indicated conditions.   
1. Thrombotic endpoint: 
a. If the patient suffers a symptomatic or asymptomatic thrombotic recurrence which 
is confirmed by cross-sectional imaging, then the study medication should be 
discontinued and the patient should be initiated on an alternate therapeutic 
anticoagulant based on guideline recommendations.  Alternate anticoagulants could 
include enoxaparin/warfarin, rivaroxaban, edoxaban or dabigratran. 
b. If the serial ultrasound imaging clearly identifies thrombus propagation which 
remains confined to the calf veins, then the study medication should be 
discontinued and the patient should be initiated on an alternate therapeutic 
anticoagulant based on guideline recommendations.   
c. During normal business hours, the patient may be unblinded by contacting the 
Central Office (see page 1 of protocol).  The Central Office will seek approval from 
the PI or a delegated Investigator prior to unblinding. During emergency 
circumstances where patient safety is felt to be compromised, study allocation can 

 
 
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be rapidly determined by drawing a heparin antiXa activity measure. If the patient is 
allocated to apixaban, the level will be elevated, unless they are not taking their 
medication. For patients allocated to placebo the levels will be undetectable.  The 
unblinding site must notify the central office of the unblinding event within 72 hours 
of becoming aware. 
 
2. Hemorrhagic endpoint: 
a. Non-major Clinically Relevant Bleed:  If the patient suffers a non-major 
clinically relevant bleed, then the study medication should be temporarily 
discontinued until the site and circumstances of the bleeding event have been 
evaluated.  If these circumstances can be rectified, then the patient can remain on 
the study medication which will be restarted as soon as clinically indicated. 
b. Major Bleed:  If the patient suffers a major bleed, then the study medication 
should be discontinued and the patient cared for as clinically appropriate.  Under 
these circumstances, the patient will be unblinded to determine the specific study 
medication (apixaban or matching placebo) by contacting the Central Office (see 
page 1 of protocol).  During emergency circumstances where patient safety is felt 
to be compromised, study allocation can be rapidly determined by drawing a 
heparin antiXa activity measure. If the patient is allocated to apixaban, the level 
will be elevated, unless they are not taking their medication. For patients allocated 
to placebo the levels will be undetectable. The unblinding site must notify the 
central office of the unblinding event within 72 hours of becoming aware.  Whether 
to restart an alternative anticoagulant will be left at the discretion of the medical 
care provider attending the patient.   
c. Life-threatening Bleed:  If the patient suffers a life-threatening bleed, then the 
study medication should be discontinued and the patient cared for as clinically 
appropriate.  During emergency circumstances where patient safety is felt to be 
compromised, study allocation can be rapidly determined by drawing a heparin 
antiXa activity measure. If the patient is allocated to apixaban, the level will be 
elevated, unless they are not taking their medication. For patients allocated to 
placebo the levels will be undetectable. The unblinding site must notify the central 
office of the unblinding event within 72 hours of becoming aware. During normal 
business hours, the patient may be unblinded by contacting the Central Office (see 
page 1 of protocol).Treatment may include the use of prothrombin complex 
concentrates (K-Centra) depending on which study medication the subject was 
receiving (apixaban or placebo). Once the specific antidote for direct oral factor Xa 
inhibitors, andexanet alpha, has been FDA approved, the use of this medicine 
would also be appropriate.   

 
 
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4.4.2 When and How to Withdraw Subjects 
Conditions under which a subject may be withdrawn from the study prior to that 
subject completing all of the study related procedures may include: 
1. Subject safety issues:   
a. Major bleeding including life threatening bleeding.  For patients suffering a 
major bleed, the clinical scenario will be reviewed by the primary care 
provider caring for the patient to determine study drug termination.  The 
site or overall investigators can also assist with this decision making.    
b. Thromboembolic Event.  For patients suffering a thromboembolic event, 
study drug should be discontinued and an alternative anticoagulant 
initiated by the health care provider caring for the patient.   
2. Failure of subject to adhere to protocol requirements. 
3. Thrombocytopenia.  For platelet counts below 50 x109/L, the patient will be 
excluded from continued participation.   
4. Development of severe renal impairment (creatinine clearance < 25 ml/min).  
Renal function assessment will not be followed for the purposes of this study 
but only if clinically indicated.   
5. Development of severe hepatic impairment (LFTs > 3x ULN).  Liver function 
assessment will not be followed for the purposes of this study but only if 
clinically indicated.   
6. Subject decision to withdraw from the study (withdrawal of consent) 
 
4.4.3 Data Collection and Follow-up for Withdrawn Subjects 
For subjects withdrawn from the study, follow-up data will be collected throughout 
the protocol defined follow-up period. This is regardless of compliance or tolerance with 
study medication, provided participants are willing to provide follow up examinations. 
This data is important to the integrity of the final study analysis since early withdrawal 
could be related to the safety profile of apixaban.  If a subject withdraws consent to 
participate in the study, for subject safety reasons, attempts will be made to obtain 
permission to collect follow up information, whenever possible.  
5 Study Drug  
5.1 Description 
Apixaban, an oral factor Xa inhibitor, will be provided as a 5 mg tablet or 
matching placebo.   
5.2 Treatment Regimen 
Patients randomized to apixaban will be treated with 10 mg twice daily for 7 days 
followed by 5 mg twice daily for 3 months.  Patients assigned to matching placebo will 
take their tablets in a similar fashion.   
5.3 Ultrasound surveillance 
Following the initial diagnostic duplex ultrasound establishing the presence of a 
calf vein thrombosis, all subjects, regardless of randomization, will undergo serial follow 

 
 
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up venous ultrasound imaging of the original involved lower extremity at 7 days, 14 days 
and 3 months.  All images will be compared to the original study by a radiologist 
dedicated to the ultrasound practice but blinded to treatment allocation.  The standard 
ultrasound imaging protocol used for clinical DVT assessment will be used for this study 
without modification.  The patient will be positioned supine with slight reversed 
Trendelenburg (10◦) on the examination table with the hip externally rotated and the 
knee slightly flexed in an outward position (“Frog leg” posture).  A linear ultrasound 
probe adjusted to the LEV setting at 9MHz will be optimized to depth, gain and focal 
zone.  Venous imaging will begin at the common femoral vein and continued throughout 
the leg and foreleg to the calf veins carefully assessing each deep venous segment.  
The great saphenous vein is also imaged in this manner however an extension of 
thrombus into this superficial vein will not be included as an efficacy endpoint.  Image 
acquisition will include grey scale cross-sectional imaging of each venous segment with 
and without compression.  Color imaging will be included for each venous segment to 
confirm patency.  Once the calf DVT is identified, both the distal and proximal most 
extent of the thrombus will be marked on the skin using a skin pen.  The thrombus 
length will then be measured and recorded by measuring the distance from the distal to 
the proximal skin mark.  For those patients with multiple calf vein involvement, the 
length of each thrombus should be measured and recorded.  Images will be compared 
side by side with the archived original study to determine whether thrombus propagation 
has occurred.  All images will be interpreted by a radiologist with expertise and 
dedication to vascular ultrasound but blinded to treatment allocation.  All images will be 
archived in our PACs system.   
 
5.4 Method for Assigning Subjects to Treatment Groups 
In general, the patient should be randomized as soon as possible after the 
baseline evaluation is completed.  Randomization should be completed and study drug 
started on the day of evaluation.   
5.4.1 Stratification 
Prior to randomization, subjects will be stratified on thrombotic risk based on the 
presence of one or more of the following characteristics:  deep vs. muscular venous 
thrombosis, postoperative status, and single vs. multiple venous segment involvement.   
5.4.2 Central Automated Randomization 
Subjects will be randomized in 1:1 ratio to either apixaban group or placebo 
group. The randomization scheme will be generated by the study statistician.  
5.5 Preparation and Administration of Study Drug 
Drug (apixaban or matching placebo) will be stored and distributed from 
McKesson to each of the 3 study sites.  This study uses a double blind design.  
Specifically, McKesson will pre-package the doses of either apixaban or matching 
placebo into bottles labeled with assigned bottle numbers, and then dispense a three 
month supply of the drug to the Mayo Clinic Pharmacy at each study site.   

 
 
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Upon randomization, the Mayo Clinic Pharmacy (MCP) at each site will be 
informed of the subject’s allocation.  The MCP pharmacist will then dispense the drug 
(apixaban or matching placebo) according to randomized assigned bottle number in a 
three month’s supply (200 tablets/bottle).  The study coordinator will then go to MCP, 
retrieve the drug and hand it to the patient.  The first dose will be given to the patient 
immediately upon receiving the medication.  Three month’s supply will be provided to 
the patient.    
For the initial 7 days, subjects will take 2 tablets (apixaban or matching placebo) 
twice daily (total of 4 tablets per day).  Thereafter patients will take one tablet twice daily 
(apixaban 5 mg or matching placebo).  Drug labeling will be according to national law 
and GMP ruling Annex 13.19.  Active study drug and placebo will be stored at 15-25°C 
(59-77°F).   
 
Subject Compliance Monitoring 
Study medication should be used in accordance with the protocol, under the 
responsibility of the investigator. The research pharmacist or any authorized person 
should maintain a complete and accurate record of the receipt of all study medication 
supplied to the site by McKesson. These records should include dates of receipt, 
batches and quantities received. The sponsor will provide bulk drug supply to 
McKesson.  McKesson will then package “open label” stock drug in bottles containing 
200 tablets of either apixaban or matching placebo.  Upon request, each site will then 
be supplied with open label drug in bottles.  Upon receipt of drug from McKesson, each 
Mayo Clinic Pharmacy site will coordinate the randomization received by the statistician 
and label the bottle and dispense blinded prescription bottle to study coordinator.  The 
study coordinator will then disperse drug to the subject.   
Sites will be supplied enough study drug to complete half of their assigned 
recruitment target.  Recruitment targets are as follows:  Rochester (150 patients), La 
Crosse (50 patients), Eau Claire (50 patients).   Once each site is nearing half of their 
recruitment target, then they will request additional drug from McKesson.  This shipment 
plan will help to redistribute available drug to the sites most actively recruiting.    
Record keeping at each site MCP will include subject number, the date, quantity 
and batch numbers of the dispensed and returned medication and the dispenser. All 
non-dispensed medication supplied to the site by McKesson should be kept securely in 
the original containers in a designated locked container until retrieved/dispensed.  
Subjects should be instructed to return all used, partially used, or unused 
medication packaging to the site.  
A log should be kept by subject number, of the date, quantity, and batch numbers 
returned (the dispensing and the return log may be combined).  For medication supplied 
to the site by McKesson, the total amount of medication used and unused should equal 
the amount received, any discrepancies should be explained in writing. All unused 
medication will be destroyed and records of shipment/receipt and or destruction will be 
maintained. 
If a dose of study medication (apixaban or matching placebo) 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.   

 
 
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5.6 Prior and Concomitant Therapy 
Non-steroid anti-inflammatory drugs (NSAIDs) and antiplatelet agents are 
discouraged. However, if indicated, aspirin up to a dosage of 165 mg/day will be 
allowed.  Dual antiplatelet therapy (P2Y12 inhibitor plus aspirin) and/or aspirin greater 
than 165 mg are not permitted.    
5.7 Packaging 
Apixaban (5 mg tablet strength or matching placebo control) will be provided in a 
HDPE-bottle containing 200 tablets to complete a total of 3 months of therapy.     
5.8 Blinding of Study  
This is a double blind placebo controlled study.  
5.8.1 Receipt of Drug Supplies 
The BMS/Pfizer will provide bulk drug supply to McKesson.  McKesson will then 
package drug pre-labeled by assigned randomization bottle numbers in bottles 
containing 200 tablets of either apixaban or matching placebo to each site.  Upon 
request, each site will then be supplied with drug in bottles, along with a shipment 
manifest of the total bottle numbers dispensed.  Upon receipt of drug from McKesson, 
each Mayo Clinic Pharmacy site will coordinate the dispensing of the blinded 
randomized treatment to study coordinator.  Upon receipt of the study treatment 
supplies, an inventory must be performed and a drug receipt log filled out by the person 
accepting the shipment at MCP.  The designated study staff will count and verify that 
the shipment contains all the items noted in the shipping invoice. Any discrepancies, 
damaged or unusable study drug in a given shipment (active drug or comparator) will be 
documented in the study files. The sponsor-investigator will be notified immediately of 
any discrepancies, damaged or unusable products that are received. Delegated 
unblinded study staff will have access to the randomization key. Through use of a Mayo 
licensed randomization software, the bottle numbers will be assigned to the designated 
site at the time of randomization using the stratification outlined in 5.4.1.   
5.8.2 Storage 
Apixaban (and matching placebo control) will be stored at MCRP 15-25°C (59-
77°F).   
5.8.3 Dispensing of Study Drug 
Upon randomization, the MCP will be informed of the subject’s allocation.  The 
MCP research pharmacist will then assemble the drug in a three month’s supply.  The 
study coordinator will then go to MCP, retrieve the drug and hand it to the patient.  The 
first dose will be given to the patient immediately upon receiving the medication.   
Apixaban 5 mg (or matching placebo) will be provided in a HDPE-bottle containing 200 
tablets.    
Regular study drug reconciliation should be performed to document drug 
assigned, drug dispensed, drug returns, and drug remaining.  This reconciliation should 
be logged on the drug reconciliation form, and signed and dated by the study team. 

 
 
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5.8.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, 
drug dispensed, drug returns, and drug remaining.  This reconciliation will be logged on 
the drug reconciliation form, signed and dated.  Any discrepancies noted will be 
documented and investigated, prior to return or destruction of unused study drug.  Drug 
destroyed on site will be documented in the study files. 
6 Study Procedures 
6.1 Visit 1 (day 0) 
At the time of the initial assessment (Randomization visit, day 0 on the flow 
chart), the complete history and physical examination performed by the health care 
provider attending the patient will be recorded by the enrolling study personnel.  Recent 
baseline laboratory data (collected within 4 weeks) will include complete blood counts 
(CBC), creatinine, and ALT (or AST).  The creatinine clearance will be calculated using 
the method of Cockcroft and Gault:   
Cockcroft-Gault GFR = (140-age) * (Wt in kg) * (0.85 if female) / (72 * Cr) 
These laboratory values must be current within 4 weeks of this initial encounter.   
6.2 Surveillance and Follow up.  
Following randomization, subjects will be assigned to either active treatment with 
apixaban or placebo control for a total of 90 days.  Each subject will then undergo follow 
up ultrasound imaging at 7 days (+/- 2 days), 14 days (+/- 2 days) and 90 days (+/- 7 
days).  This ultrasound imaging study will focus on venous thrombus propagation into 
the proximal venous segments.  At each follow up, all venous segments of the involved 
lower extremity will be imaged.  This imaging should be performed at a site participating 
in this research project.   Patients will be called at Days 30 & 60 (+/- 7 days) to check 
their health status, adverse reactions and medication compliance.    
Patients will be instructed to report to the clinic immediately if they had any 
bleeding or symptoms of recurrent deep-vein thrombosis, pulmonary embolism, or both. 
All suspected episodes of recurrent thrombosis will be investigated with the use of 
objective tests, according to prespecified diagnostic algorithms.  At 3 months (+/- 7 
days), patients will return for a routine clinically indicated ultrasound and clinical 
assessment.   
 
Study Activity 
Day 0 
Day 7  
(± 2 days) 
Day 14   
(± 2 days) 
Day 30  
(± 7 days) 
Day 60  
(± 7 days) 
Day 90  
(± 7 days) 
Informed consent 
X 
 
 
 
 
 
History 
X 
 
 
 
 
 
Concurrent meds 
X 
 
X 
 
X 
 
X 
 
X 
 
X 

 
 
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Collect data from 
clinical physical 
exam (Ht, Wt, BSA, 
VS) 
X 
 
 
 
 
 
Collect Lab Values 
(CBC, creatinine, 
ALT/AST)a 
 
 
Xa 
 
 
 
 
 
Adverse event 
evaluation 
 
 
X 
 
X 
 
X 
 
X 
 
X 
B-HCG 
 
Xb 
 
 
 
 
 
Drug dispensing 
and collection of 
any unused drug 
X 
 
 
 
 
X 
Ultrasoundc 
 
X 
 
X 
 
X 
 
 
 
X 
Telephone survey 
(appendix A) 
 
 
 
X 
X 
 
a = Collect data from clinical testing in the last 4 weeks. 
b = Women of child bearing potential only. If not done clinically in the last 2 weeks. 
c = The baseline ultrasound will be requested and performed by the provider caring for the patient.  This 
will be a clinically indicated study and will not be repeated for study purposes.  This US will serve as the 
baseline imaging study for trial purposes.   
 
 

 
 
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7 Statistical Considerations 
7.1 Sample Size Determination 
 An anticipated venous thromboembolic event rate of 12.6% within 3 months for 
patients randomized to standard medical observation and placeo is expected (Table 
Below). The composite venous thrombosis event rate of 12.6% includes a thrombus 
propagation rate of 5.4%, pulmonary embolism rate of 0.5% and recurrent venous 
thrombosis rate of 6.7% over this time interval.   Specifically, for sample size 
calculations, we consider an event rate of 10% for the placebo arm.  By comparison, 
thromboembolic outcomes in the AMPLIFY trial for those subjects randomized to 
apixaban was 2.3% at 6 months. We hypothesize the apixaban arm in this study will 
result in a 3 month event rate in the range of 1.0% to 2.3%. Specifically, for sample size 
calculations, we consider an event rate of 1.6% for the apixaban arm.   
 
 
 
The detailed listing of assumptions used to estimate the sample size are as follows: 
• 3 month thromboembolic outcomes for the placebo arm = 10.0% 
• 3 month thromboembolic outcomes for the apixaban arm = 1.6% 
• Equal allocation to both treatment groups 

 
 
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• One interim analysis using O’Brien-Flemming-like alpha spending function 
conducted after 40% of the enrolled participants have their 90 day outcome 
assessed (40% information fraction)  
• An overall two-sided significance level of 0.05 with a final adjusted alpha of 
0.0492 (after interim analysis correction) 
• Target power = 80% 
• Normal approximation to the proportions, two independent groups, no continuity 
correction  
Based on the assumptions above, a sample size of 121 per arm would be required. We 
round this estimate to 125/group (250 total) to account for minor attrition to the intention 
to treat analysis set including subject dropout and missing data.   
 
7.2 Statistical Methods 
 
7.2.1 Primary Hypothesis:  
 
We hypothesize that apixaban 5 mg twice daily is associated with a significantly lower 
rate of the primary composite efficacy outcome compared to matched placebo in 
patients with calf DVT.   
 
7.2.1.2  Primary Efficacy Analysis: All patients randomized to receive at least one 
dose of apixaban 5 mg or matching placebo control will be included in the primary 
analysis under intention to treat (see analysis sets below).  The analysis of the primary 
composite endpoint will only include events occurring during the 3 months of study 
medication use.   
 
Frequency of the primary composite efficacy endpoint will be tabulated by treatment 
arm without regard to the time the event was observed within the 3 month study period. 
The Cochran-Mantel-Haenszel test will be used to compare the event rates by 
treatment group. The pooled estimate of the odds ratio will be used as the primary 
measure of association for the study.   
 
An exploratory analysis will investigate the time to event is defined as the time from 
randomization to the first occurrence of a primary composite efficacy outcome event.  
Patients who were lost to follow-up or who withdrew consent before the end of the three 
month treatment period will be censored at the last day the patient had a complete 
assessment for study outcomes within the 3 month study period.  The incidence curves 
of VTE events will be plotted using the Kaplan-Meier estimator by treatment group.    
The difference in the incidences of the primary composite outcome at 3 months 
between treatment arms will be estimated and tested using a normal approximation of 
the binomial distribution.  
   
 

 
 
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7.2.1.3  Safety Analysis:  All patients who received at least one dose of study 
medication will be included in the safety analysis. The analysis of major bleeding and 
clinically relevant non-major bleeding events will include those events which occurred 
during the 3 month study period. Major bleeding events observed later will be described 
separately.   
 
Frequency of major bleeding and clinically relevant non-major bleeding will be tabulated 
by treatment arm.  The incidence of major bleeding and clinically relevant non-major 
bleeding will be summarized as a combined endpoint and separate endpoints by 
treatment arm.  The difference in the incidences of the combined endpoint at 3 months 
between treatment arms will be estimated and tested using a normal approximation of 
the binomial distribution.  
 
The outcome of net clinical benefit or harm will be assessed as the composite of the 
primary efficacy outcome or the principal safety outcome up to day 90.  The difference 
in the incidences of the combined endpoint at 3 months between treatment arms will be 
estimated and tested using a normal approximation of the binomial distribution. All tests 
will be conducted at the two-sided 0.05 significance level. 
 
Multiplicity 
 
No correction to the type I error rate will be applied to account for the primary and 
secondary endpoints. Accordingly, all analyses will utilize a two-sided alpha=0.05 level 
of significance with exception of the primary analysis. For the primary analysis, the final 
alpha level will be determined by the alpha spending function as defined in the following 
section.   
 
Interim Analysis 
A partially blinded interim analysis will be conducted when 40% of the planned 
participants complete the 90 day outcome assessment (i.e., after the 100th participant 
completes the 90 day outcome). The O’Brien-Fleming-like alpha spending function will 
be used to determine the final alpha level. At time of study planning, 40% information 
fraction results in an interim stopping p-value of <0.00079. This value may vary slightly 
depending on the final data included in interim analysis. For partial blinding, the actual 
treatment codes will be replaced by generic “Treatment A” and “Treatment B” labels by 
the unblinded statistician for the DSMB’s review. In the event a full unblinding of the 
study is desired, the DSMB will be able to request the actual treatment assignments 
from the unblinded study statistician.  
7.3 Subject Population(s) for Analysis 
The subject populations whose data will be subjected to the study analysis both 
for the primary efficacy and safety analyses will include all randomized population under 
the intention to treat principle.  Any subject randomized into the study, regardless of 
whether they received study drug will be included in the primary efficacy analysis 
provided the participant does not withdraw consent for use of any data collected in the 
course of the study or as otherwise required by institutional review board determination. 

 
 
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The per protocol analysis set will also be utilized for exploratory analyses. For this 
analysis, the participant will be expected to have obtained all outcome measurements 
over the 90 days along with >80% compliance with medication. Furthermore, the 
participant will need to not have a three day period (6 half-lives of apixaban) with no 
study medication.  We will also perform a “full analysis set” and an “on-treatment” 
analysis for the study outcomes. For the purpose of this study, the full analysis set will 
be determined in accordance with ICH E9 guidelines. The on-treatment analysis data 
set will include subjects who are randomized to study and take at least one dose of 
study medication.     
 
8 Safety and Adverse Events 
8.1 Definitions 
1. Adverse Events.  An Adverse Event (AE) is defined as any new untoward 
medical occurrence or worsening of a preexisting medical condition in a clinical 
investigation participant administered study drug and that does not necessarily have 
a causal relationship with this treatment. An AE can therefore be any unfavorable 
and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of investigational product, whether or not 
considered related to the investigational product.  The causal relationship to study 
drug is determined by a physician and should be used to assess all adverse events 
(AE). The casual relationship can be one of the following: 
 
Related: There is a reasonable causal relationship between study drug 
administration and the AE. 
 
Not related: There is not a reasonable causal relationship between study drug 
administration and the AE.  
 
The term "reasonable causal relationship" means there is evidence to suggest a 
causal relationship.  
 
Adverse events can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a subject. (In order to prevent reporting 
bias, subjects should not be questioned regarding the specific occurrence of one or 
more AEs.) 
 
2. Serious Adverse Events. Serious Adverse Event (SAE) is any untoward 
medical occurrence; results in death; is life-threatening (defined as an event in which 
the participant was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it were more severe); requires 
inpatient hospitalization; or causes prolongation of existing hospitalization (see 
NOTE below); results in persistent or significant disability/incapacity; is a congenital 

 
 
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anomaly/birth defect; is an important medical event (defined as a medical event(s) 
that may not be immediately life-threatening or result in death or hospitalization but, 
based upon appropriate medical and scientific judgment, may jeopardize the subject 
or may require intervention [eg, medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) (Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization).  
 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via 
the study drug is an SAE.  
 
Although pregnancy, overdose, adverse events of special interest, and cancer are 
not always serious by regulatory definition, these events must be handled as SAEs. 
Any component of a study endpoint that is considered related to study therapy 
should be reported as an SAE (eg, death is an endpoint, if death occurred due to 
anaphylaxis, anaphylaxis must be reported). 
 
The following hospitalizations are not considered SAEs in BMS clinical studies:  
a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening 
event); elective surgery, planned prior to signing consent admissions as per protocol 
for a planned medical/surgical procedure routine health assessment requiring 
admission for baseline/trending of health status (eg, routine colonoscopy); 
medical/surgical admission other than to remedy ill health and planned prior to entry 
into the study. Appropriate documentation is required in these cases. 
 
Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (eg, lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative 
reason). 
 
3. Adverse Events of Special Interest.  In this study, the following adverse events 
are to be reported to BMS as serious events, regardless of whether these reports 
are classified as serious or unexpected: Potential or suspected cases of liver injury 
including but not limited to liver test abnormalities, jaundice, hepatitis or cholestasis. 
 
4. Pregnancy.  If, following initiation of the investigational product, it is 
subsequently discovered that a study participant is pregnant or may have been 
pregnant at the time of investigational product exposure, including during at least 5 
half-lives after product administration, the investigational product will be permanently 
discontinued in an appropriate manner (eg, dose tapering if necessary for 
participant).  
The investigator must immediately notify Worldwide.Safety@bms.com of this event 
via, MedWatch or appropriate Pregnancy Surveillance Form in accordance with SAE 

 
 
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reporting procedures. Protocol-required procedures for study discontinuation and 
follow-up must be performed on the participant.  Follow-up information regarding the 
course of the pregnancy, including perinatal and neonatal outcome and, where 
applicable, offspring information must be reported on the, MedWatch or appropriate 
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 will 
be collected on the Pregnancy Surveillance Form. In order for Sponsor or designee 
to collect any pregnancy surveillance information from the female partner, the female 
partner must sign an informed consent form for disclosure of this information.  
 
5. Overdose.  An overdose is defined as the accidental or intentional administration 
of any dose of a product that is considered both excessive and medically important. 
All occurrences of overdose must be reported as an SAE. 
 
6. Non-serious Adverse Event.  Non-serious Adverse Events (AE) are to be 
provided to BMS in aggregate via interim or final study reports as specified in the 
agreement or, if a regulatory requirement [eg, IND US trial] as part of an annual 
reporting requirement.  
Non-serious AE information should also be collected from the start of a placebo 
lead-in period or other observational period intended to establish a baseline status 
for the subjects.  A non-serious adverse event is an AE not classified as serious.  
 
7. Serious Adverse Event Collection and Reporting.  Following the subject’s 
written consent to participate in the study, all SAEs, whether or not related to the 
BMS product under study, must be collected, including those thought to be 
associated with protocol-specified procedures. SAEs must be recorded on CIOMS or 
FDA MedWatch 3500A Form and reported to BMS (or designee) within 1 business 
day to comply with regulatory requirements. A form should be completed for any 
event where doubt exists regarding its status of seriousness.  Although overdose 
and cancer are not always serious by regulatory definition, these events should be 
recorded on a form and reported to BMS within 1 business day.     
All SAEs must be reported by confirmed facsimile (fax) transmission or reported via 
electronic mail to: 
SAE Email Address: Worldwide.Safety@BMS.com  
SAE Facsimile Number:  1-609-818-3804  
 
If only limited information is initially available, follow-up reports may be required.  
For studies capturing SAEs through electronic data capture (EDC), electronic 
submission is the required method for reporting.  The paper forms should be used 
and submitted immediately, only in the event the electronic system is unavailable for 
transmission.  When paper forms are used, the original paper forms are to remain on 
site. 
If it is discovered a patient is pregnant or may have been pregnant at the time of 
exposure to the BMS product under study, the pregnancy, AEs associated with 
maternal exposure and pregnancy outcomes must be recorded on a Pregnancy 

 
 
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Surveillance Form and reported to BMS (or designee) within 1 business day by 
confirmed fax or reported via electronic mail to Worldwide.Safety@BMS.com. If only 
limited information is initially available, follow-up reports may be required. The 
original BMS forms are to remain on site.  Follow-up information should be obtained 
on pregnancy outcomes for one year following the birth of the offspring.  
Any pregnancy that occurs in a female partner of a male study participant should be 
reported to BMS. Information on this pregnancy will be collected on the Pregnancy 
Surveillance Form. 
 
8. Non-serious Adverse Event Collection and Reporting.  The collection of non-
serious AE information should begin at initiation of study drug. All non-serious 
adverse events (not only those deemed to be treatment-related) should be collected 
continuously during the treatment period and for a minimum of 30 days following the 
last dose of study treatment.  
Non-serious AEs should be followed to resolution or stabilization, or reported as 
SAEs if they become serious. Follow-up is also required for non-serious AEs that 
cause interruption or discontinuation of study drug and for those present at the end 
of study treatment as appropriate.  
 
Nonserious Adverse Events are provided to BMS via annual safety reports (if 
applicable), and interim or final study reports. 
 
9. SAE Reconciliation.  The investigator will reconcile the clinical database SAE 
cases transmitted to BMS Global Pharmacovigilance (GPV&E). Frequency of 
reconciliation will be done every three months and 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@bms.com. 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. 
Non-serious Adverse Event Collection and Reporting 
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported to BMS as 
such. 
The following laboratory abnormalities should be documented and reported appropriately: 
• 
any laboratory test result that is clinically significant or meets the definition of an SAE 
• 
any laboratory abnormality that required the participant to have study drug discontinued or 
interrupted 
• 
any laboratory abnormality that required the subject to receive specific corrective therapy.  

 
 
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It is expected that wherever possible, the clinical rather than laboratory term would be used by 
the reporting investigator (eg, anemia versus low hemoglobin value). 
 
 
10.  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 non-serious or serious AE, as appropriate, and 
reported accordingly.  
 
8.2 Recording of Adverse Events 
At each contact with the subject, the study team must seek information on 
adverse events by specific questioning.  Information on all adverse events should be 
recorded immediately in the source document, and also in the appropriate adverse 
event section of the case report form (CRF).  All clearly related signs, symptoms, and 
abnormal diagnostic, laboratory or procedure results should recorded in the source 
document. 
All adverse events occurring during the study period must be recorded.  The 
clinical course of each event should be followed until resolution, stabilization, or until it 
has been ultimately determined that the study treatment or participation is not the 
probable cause.  Serious adverse events that are still ongoing at the end of the study 
period must be followed up, to determine the final outcome.  Any serious adverse event 
that occurs after the study period and is considered to be at least possibly related to the 
study treatment or study participation should be recorded and reported immediately. 
8.3 Reporting of Serious Adverse Events and Unanticipated Problems 
When an adverse event has been identified, the study team will take 
appropriated action necessary to protect the study participant and then complete the 
Study Adverse Event Worksheet and log.  The sponsor-investigator will evaluate the 
event and determine the necessary follow-up and reporting required. 
 
8.3.1 Sponsor-Investigator reporting: notifying the Mayo IRB 
The sponsor-investigator will report to the Mayo IRB any UPIRTSOs and Non-
UPIRTSOs according to the Mayo IRB Policy and Procedures.  Any serious adverse 
event (SAE) which the Principal Investigator has determined to be a UPIRTSO will be 
reported to the Mayo IRB as soon as possible but no later than 5 working days after the 
investigator first learns of the problem/event. 
 
Information collected on the adverse event worksheet (and entered in the research 
database):  
• Subject’s name:  
• Medical record number:  

 
 
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• Disease/histology (if applicable):  
• The date the adverse event occurred:  
• Description of the adverse event:  
• Relationship of the adverse event to the research (drug, procedure, or 
intervention):  
• If the adverse event was expected:  
• The severity of the adverse event: (use a table to define severity scale 1-5) 
• If any intervention was necessary:  
• Resolution: (was the incident resolved spontaneously, or after discontinuing 
treatment) 
• Date of Resolution:  
 
The sponsor-investigator will review all adverse event reports to determine if specific 
reports need to be made to the IRB and FDA.  The sponsor-investigator will sign and 
date the adverse event report when it is reviewed.  For this protocol, only directly related 
SAEs/UPIRTSOs will be reported to the IRB. 
8.3.2 Sponsor-Investigator reporting: Notifying the FDA 
The sponsor-investigator will report to the FDA all unexpected, serious suspected 
adverse reactions according to the required timelines, formats and requirements. 
Unexpected fatal or life threatening suspected adverse reactions where there is 
evidence to suggest a causal relationship between the study drug/placebo and the 
adverse event, will be reported as a serious suspected adverse reaction.  This will be 
reported to the FDA on FDA Form 3500A, no later than 5 business days after the 
sponsor-investigator’s initial receipt of the information about the event. 
Other unexpected serious suspected adverse reactions where there is evidence 
to suggest a causal relationship between the study drug/placebo and the adverse event, 
will be reported as a serious suspected adverse reaction.  This will be reported to the 
FDA on FDA Form 3500A, no later than 15 business days after the sponsor-
investigator’s initial receipt of the information about the event. 
Any clinically important increase in the rate of serious suspected adverse 
reactions over those listed in the protocol or product insert will be reported as a serious 
suspected adverse reaction.  This will be reported to the FDA on FDA Form 3500A no 
later than 15 business days after the sponsor-investigator’s initial receipt of the 
information about the event.   
Findings from other studies in human or animals that suggest a significant risk in 
humans exposed to the drug will be reported.  This will be reported to the FDA on FDA 
Form 3500A, no later than 15 business days after the sponsor-investigators initial 
receipt of the information about the event. 
8.4 Medical Monitoring 
The Principal Investigators will oversee the safety of the study.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events 
as noted above, as well as the construction and implementation of a site data and 

 
 
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safety-monitoring plan (see section 10  “Study Monitoring, Auditing, and Inspecting”).  
Medical monitoring will include a regular assessment of the number and type of serious 
adverse events. 
9 Data Handling and Record Keeping 
9.1 Confidentiality 
Information about study subjects will be kept confidential and managed according 
to the requirements of the Health Insurance Portability and Accountability Act of 1996 
(HIPAA).  Those regulations require a signed subject authorization informing the subject 
of the following:  
• What protected health information (PHI) will be collected from subjects in this 
study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI.  
In the event that a subject revokes authorization to collect or use PHI, the investigator, 
by regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization.  For subjects that have revoked authorization to collect or use 
PHI, attempts should be made to obtain permission to collect at least vital status (long 
term survival status that the subject is alive) at the end of their scheduled study period. 
9.2 Source Documents 
Source data is all information, original records of clinical findings, observations, 
or other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial.  Source data are contained in source documents.  Examples of these original 
documents, and data records include: hospital records, clinical and office charts, 
laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic 
negatives, microfilm or magnetic media, x-rays, subject files, and records kept at the 
pharmacy, at the laboratories, and at medico-technical departments involved in the 
clinical trial. 
9.3 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the 
study.  All data requested on the CRF must be recorded.  All missing data must be 
explained.  If a space on the CRF is left blank because the procedure was not done or 
the question was not asked, write “N/D”.  If the item is not applicable to the individual 
case, write “N/A”.  All entries should be printed legibly in black ink.  If any entry error has 
been made, to correct such an error, draw a single straight line through the incorrect 
entry and enter the correct data above it.  All such changes must be initialed and dated.  
Do not erase or use “white-out” for errors.  For clarification of illegible or uncertain 
entries, print the clarification above the item, then initial and date it.  If the reason for the 
correction is not clear or needs additional explanation, neatly include the details to 
justify the correction. 

 
 
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Data Management 
A RedCap database system (DMS) for the collection, storage and management 
of all study data will be developed at Mayo Clinic Rochester. The RedCap database will 
provide for data entry (including data entry at the trial sites using a web portal and 
immediate storage of the data in the central database), data security, and reporting.  
The data management team will develop a data validation plan, rule set specifications, 
and programming logic to implement data validation rules. The rule set will include 
checks for missing fields, range checks, skip pattern-logic, and inter and intra form 
checks.   
 
9.4 Records Retention 
The sponsor-investigator will maintain records and essential documents related 
to the conduct of the study.  These will include subject case histories and regulatory 
documents. 
 
The sponsor-investigator will retain the specified records and reports for; 
1. Up to 2 years after shipment and delivery of the drug for investigational use is 
discontinued and the FDA has been so notified. OR 
2. As outlined in the Mayo Clinic Research Policy Manual –“Access to and 
Retention of Research Data Policy” 
   
Whichever is longer. 
 
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
This study will be internally monitored on a routine basis during the conduct of 
the trial.  Clinical trial monitoring requires review of the study data generated throughout 
the duration of the study to ensure the validity and integrity of the data along with the 
protection of human research subjects.  This will assist sponsor-investigators in 
complying with Food and Drug Administration regulations. 
The investigator will allocate adequate time for such monitoring activities.  The 
Investigator will also ensure that the monitor or other compliance or quality assurance 
reviewer is given access to all the study-related documents and study related facilities 
(e.g. pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct the 
monitoring visit. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by 
the IRB, the sponsor, and government regulatory agencies, of all study related 
documents (e.g. source documents, regulatory documents, data collection instruments, 

 
 
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study data etc.).  The investigator will ensure the capability for inspections of applicable 
study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
Participation as an investigator in this study implies acceptance of potential 
inspection by government regulatory authorities and applicable compliance offices. 
11 Ethical Considerations 
This study is to be conducted according to United States government regulations 
and Institutional research policies and procedures.  This protocol and any amendments 
will be submitted to a properly constituted local Institutional Review Board (IRB), in 
agreement with local legal prescriptions, for formal approval of the study.  The decision 
of the IRB concerning the conduct of the study will be made in writing to the sponsor-
investigator before commencement of this study. 
All subjects for this study will be provided a consent form describing this study 
and providing sufficient information for subjects to make an informed decision about 
their participation in this study.  This consent form will be submitted with the protocol for 
review and approval by the IRB for the study.  The formal consent of a subject, using 
the Approved IRB consent form, must be obtained before that subject undergoes any 
study procedure.  The consent form must be signed by the subject and the individual 
obtaining the informed consent. 
 
12 Study Finances 
12.1 Funding Source 
The (BMS/Pfizer American Thrombosis Investigator Initiated Research Program 
(ARISTA-USA) is established to fund innovative medical research from investigators in 
the United States. This study is funded through the competitive request for application 
(RFA) through this Bristol Myers Squibb/Pfizer Alliance funding program.   
13 Publication Plan 
The success of this trial will depend largely on the number and quality of its 
scientific publications and presentations. The purpose of the policy established is to 
encourage and facilitate the presentation of trial analyses while providing guidelines that 
ensure appropriate use of the data, timely completion of manuscripts and presentations, 
equitable access to authorship, and adherence to established principles of authorship 
using the ICMJE criteria. 
14 References 
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Ferranti S, DesprésJ-P, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jiménez 
MC, Judd SE, Kissela BM, LichtmanJH, LisabethLD, Liu S, Mackey RH, Magid DJ, 
McGuire DK, Mohler ER III, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar 
RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, 
Sorlie PD, Stein J, TowfighiA, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB; on 
behalf of the American Heart Association Statistics Committee and Stroke Statistics 

 
 
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Subcommittee. Heart disease and stroke statistics—2016 update: a report from the 
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Hull R, Delmore T, Genton E, Hirsh J, Gent M, Sackett D, McLoughlin D, 
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Lagerstedt CI, Olsson CG, Fagher BO, Oqvist BW, Albrechtsson U. Need for 
long-term anticoagulant treatment in symptomatic calf-vein thrombosis.  Lancet. 1985 
Sep 7;2(8454):515-8. 
13. 
Ferrara F, Meli F, Amato C, Cospite V, Raimondi F, Novo G, Novo S. Optimal 
duration of treatment in surgical patients with calf venous thrombosis involving one or 
more veins.  Angiology. 2006;57:418-23. 
14. 
Schwarz T, Buschmann L, Beyer J, Halbritter K, Rastan A, Schellong S.Therapy 
of isolated calf muscle vein thrombosis: a randomized, controlled study. J Vasc Surg. 
2010;52:1246-50.  

 
 
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15. 
Righini M, Galanaud JP, Guenneguez H, Brisot D, Diard A, Faisse P, Barrellier 
MT, Hamel-Desnos C7, Jurus C, Pichot O, Martin M, Mazzolai L, Choquenet C, 
Accassat S, Robert-Ebadi H, Carrier M, Le Gal G, Mermilllod B, Laroche JP, 
Bounameaux H, Perrier A, Kahn SR, Quere I. Anticoagulant therapy for symptomatic 
calf deep vein thrombosis (CACTUS): a randomised, double-blind, placebo-controlled 
trial.  Lancet Haematol. 2016;3:e556-e562.  
16. 
Galanaud JP, Quenet S, Rivron-Guillot K, Quere I, Sanchez Muñoz-Torrero JF, 
Tolosa C, Monreal M; RIETE INVESTIGATORS.  Comparison of the clinical history of 
symptomatic isolated distal deep-vein thrombosis vs. proximal deep vein thrombosis 
in 11 086 patients.  J Thromb Haemost. 2009;7:2028-34.  
17. 
Palareti G, Cosmi B, Lessiani G, Rodorigo G, Guazzaloca G, Brusi C, Valdré L, 
Conti E, Sartori M, Legnani C. Evolution of untreated calf deep-vein thrombosis in 
high risk symptomatic outpatients: the blind, prospective CALTHRO study.  Thromb 
Haemost. 2010;104:1063-70.  
18. 
Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, 
Raskob GE, Weitz JI; AMPLIFY-EXT Investigators. Apixaban for extended treatment 
of venous thromboembolism.  N Engl J Med. 2013;368:699-708.  
19. 
Heit JA, Mohr DN, Silverstein MD, Petterson TM, O’Fallon WM, Melton LJ III. 
Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a 
population-based cohort study. Arch Intern Med. 2000;160(6):761-768. 
20.   Soosainathan A, Moore HM, Gohel MS, Davies AH.  Scoring systems for the post-
thrombotic syndrome.  J Vasc Surg 2013;57:254-61. 
21. Schulman S, and Kearon C. Definition of major bleeding in clinical investigations of 
antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 
2005;3:692-694. 
 
 

 
 
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Appendix A.  Telephone Script: 
 
Protocol Title: A Phase IV, Randomized, Double Blind Study Evaluating the Safety and 
Efficacy of Apixaban in Subjects with Calf Vein Thrombosis 
Principal Investigator: Robert McBane, MD 
 
Completed By: _____________________________ 
 
Date: ____________________ 
Circle One: Day 7 
Day 14  
Day 30  
Day 60  
Day 90 
 
“Good morning/afternoon.  This is ___________________ calling from Mayo Clinic 
Rochester/Eau Claire/La Cross.  May I speak to__________?” (If participant is there proceed 
to the following) 
 
“I would like to ask you a few questions regarding your blood thinner medication, you are taking 
for the clinical trial in which you have been enrolled. This will allow us to gather very important 
information about the safety and benefit of using this medication in treating and preventing 
blood clots.”   
 
I would like to ask these questions related to our study after confirming your name:  
 
__________________________________________   
 
1. Since your last visit, have you missed any doses of your blood thinner medication? 
____ Yes,  
If yes, approximately how many doses do you estimate that you have missed? __ 
____ No, I have not missed any doses of medication 
 
2. Since your last visit, have you had another blood clot problem? 
____ Yes, a DVT 
____ Yes, a PE 
____ Both a DVT and a PE 
____ Yes, something else (e.g. an arterial clot) 
____ No, I have not had any more clots.  
 
3. While you have been taking this medication as recommended, have you experienced any 
major bleeding which required hospitalization or blood transfusion? 
 
____ Yes  
If yes, please describe: _____________________________ 
____ No  
 
4. While you have been taking this medication as recommended, have you experienced any 
bleeding other than from injury? 
____ Yes,  
If yes, please describe_____________________________ 
____ No  
 
 
 

 
 
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Robert D. McBane MD 
 
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5. Which of the following best applies to your current activity rating: 
A. ____ Fully active, able to carry on all pre-disease performance without restriction. 
B. ____ Restricted in physically strenuous activity, but able to walk and to carry out work 
 
  of a light or sedentary nature (for example, light house work, or office work). 
C. ____ Able to walk and capable of all self-care but unable to carry out any work  
 
 
  activities. Up and about more than 50% of waking hours. 
D. ____ Capable of only limited self-care, confined to bed or chair more than 50% of  
 
 
  waking hours. 
E. ____ Completely disabled. Cannot carry on any self-care. Totally confined to bed or   
 
  chair. 
 
6. Have you started any new medications?   
____ Yes  
If yes, please list: __________________________________________________ 
____ No 
 
7. Have you had any new leg swelling? 
____ Yes,  
If yes, suggest that the patient see their medical provider 
____ No 
 
8. Have you had any new chest pain or shortness of breath? 
____ Yes,  
If yes, suggest that the patient see their medical provider 
____ No 
 
9.  On a scale of 0 – 10, what is your current pain level for the involved leg with the blood clot? 
(circle one) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
 
 
 
Do you have any questions for me? 
 
 
Thank you for participating in our study. 
 
 
 
 
 
 
 
 

 
 
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Robert D. McBane MD 
 
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Appendix B1.  Case Report Form;  Initial data 
Date Completed: _________________________    Completed By: ___________________________ 
Name:  _______________________________ 
Birth date: ____________________________  
Gender:   1
Female     2
Male 
Height (cm): ____________________________ 
Weight (kg): ____________________________ 
Qualifying Event: Has the patient had a documented calf DVT confirmed by imaging? (check one)  
    1
Yes     2
No 
If yes: Date diagnosed: (mm/dd/yyyy) __ __/__ __/__ __ __ __ 
Location of the DVT 
 
 
Leg involved (check one)   1
Right      2
Left   3
Bilateral    
 
 
Lower extremity deep vein involved (check all that apply and provide length of thrombus in cm)    
 
 
 
1
Posterior Tibial      Length  ___________ cm 
 
 
 
2
Peroneal     
Length  ___________ cm 
 
 
 
3
Anterior Tibial      
Length  ___________ cm 
 
 
 
4
Gastrocnemius    
Length  ___________ cm 
 
 
 
5
Soleal      
 
Length  ___________ cm 
 
 
Was there evidence of proximal vein involvement (popliteal, femoral, ilial vein)   1
Yes     2
No 
How was the thrombus confirmed?  
1
Utrasound    2
 CT 3
MRI    
Pain assessment 
On a scale of 0 – 10, what is your current pain level for the involved leg with the blood clot? (circle one) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Clinical Characteristics 
 
 
No identified risk factors (unprovoked, check one)    
 
1
Yes     2
No 
 
 
Surgery (within past 3 months) (check one)    
 
 
1
Yes     2
No 
 
 
Trauma (within past 3 months) (check one)    
 
 
1
Yes     2
No  
 
 
Travel > 6 hrs (within past 3 months) (check one)   
 
1
Yes     2
No 
 
 
Prior personal history of VTE (check one)    
 
 
1
Yes     2
No  
 
 
Family history of VTE (check one)    
 
 
 
1
Yes     2
No 
 
 
Estrogen therapy(check one)      
 
 
 
1
Yes     2
No 
 
 
Postpartum (within 6 weeks of delivery) (check one)    
 
1
Yes     2
No  
 
 
Hospitalization (within past 3 months) (check one)    
 
1
Yes     2
No 
 
 
Past Cancer history (check one)  
 
    
 
1
Yes     2
No 
 
 
Known thrombophilia (check one) 
 
    
 
1
Yes     2
No 
 
 
 
Describe ________________________________ 
 
 
Inflammatory bowel disease (check one) 
    
 
1
Yes     2
No 
Laboratory Data 
 
 
Date collected (mm-dd-yr): ___ ___-___ ___-___ ____ 
CBC:  Hgb__________  WBC__________ Platelet______________  
Creatinine:  __________  ALT: _______________ AST:____________  

 
 
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Robert D. McBane MD 
 
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Smoking status (check one)   1
active smoker  2
former smoker  3
never smoker    
 

 
 
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Robert D. McBane MD 
 
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Appendix B2.  Case Report Form;  Follow up data 
Date Completed: _________________________ 
Completed By: ___________________________ 
 
Circle One:  
Day 7  
Day 14  
Day 30  
Day 60  
Day 90        Day 365 
Lower extremity deep vein involved (check all that apply and provide length of thrombus in cm)    
 
 
 
1
Posterior Tibial      Length  ___________ cm 
 
 
 
2
Peroneal     
Length  ___________ cm 
 
 
 
3
Anterior Tibial      
Length  ___________ cm 
 
 
 
4
Gastrocnemius    
Length  ___________ cm 
 
 
 
5
Soleal      
 
Length  ___________ cm 
Was there evidence of DVT propagation confirmed by imaging? (check one)      1
Yes     2
No 
If yes, which veins were involved (check all that apply)?  
 
 
 
1
Popliteal 
 
 
 
2
Femoral  
 
 
 
3
Iliac  
 
 
 
4
IVC 
Pain assessment 
On a scale of 0 – 10, what is your current pain level for the involved leg with the blood clot? (circle one) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Has patient had a documented recurrent venous thrombosis confirmed by imaging? (check one)  
    1
Yes     2
No 
 
If yes: Date diagnosed: (mm/dd/yyyy) __ __/__ __/__ __ __ __ 
 
 
Pulmonary Embolism (check one)   1
Yes     2
No 
 
 
Lower extremity deep vein thrombosis (check one)   1
Yes     2
No 
 
 
Upper extremity deep vein thrombosis (check one)   1
Yes     2
No 
 
 
(jugular, innominate, subclavian, axillary, brachial) 
 
 
Splanchnic vein thrombosis (check one)   1
Yes     2
No 
 
 
(hepatic, portal, splenic, mesenteric, renal, gonadal) 
 
 
Cerebral vein thrombosis 1
Yes     2
No 
 
 
      Fatal PE: (check one)     1
Yes     2
No 
 
      Was the VTE recurrence: (check one)     1
Symptomatic     2
 Incidental 
 
      How was the thrombus confirmed? 
 
 
1
Utrasound    2
 CT 3
MRI   4
 VQ scan  5
Surgery   6
 Autopsy 
 
      Arterial clot: (check one)     1
Yes     2
No 
 
 
If Yes, (check all that apply) 
MI 
 
 
 
 
TIA/Stroke 
 
 
 
 
Peripheral embolism 
 
 

 
 
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Robert D. McBane MD 
 
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Has patient had a major bleed? (check one)   1
Yes     2
No 
 
If Yes, date of major bleed: (mm/dd/yyyy) __ __/__ __/__ __ __ __ 
 
If Yes (check all that apply) 
Intracranial (intracerebral (hemorrhagic stroke), subarachnoid, subdural) 
 
 
 
 
Intraspinal/epidural 
 
 
 
 
Intraocular 
 
 
 
 
Intraarticular 
 
 
 
 
Intramuscular with compartment syndrome 
 
 
 
 
Retroperitoneal 
 
 
 
 
Pericardial 
 
 
 
 
Fatal bleeding 
 
 
 
 
GI 
 
 
 
 
GU 
 
 
 
 
Pulmonary 
 
 
 
 
Other   
Specify: _______________________ 
 
 
 
 
Has patient had a clinically relevant non-major bleed? (check one)   1
Yes     2
No 
 
If Yes, date of clinically relevant non-major bleed: (mm/dd/yyyy) __ __/__ __/__ __ __ __ 
 
If Yes, what were the consequences (check all that apply) 
 
 
 
 
 
 Required medical intervention 
 
 
 
 
 Unscheduled contact with health care team 
 
 
 
 
 Temporary cessation of study treatment 
 
 
Has patient had a minor bleed? (check one)   1
Yes     2
No 
 
If Yes, date of minor bleed: (mm/dd/yyyy) __ __/__ __/__ __ __ __ 
 
Last Date (any modality of) protocol therapy was given: (mm/dd/yyyy) __ __/__ __/__ __ __ __ 
(date of last treatment dose on this study or date decision made to stop protocol treatment)