Apixaban for the Treatment of Venous Thromboembolism in Patients With Cancer: A Prospective Randomized Open Blinded End-Point (Probe) Study
Phase: PHASE3
Conditions: Venous Thromboembolism
Sponsor: Fadoi Foundation, Italy

            
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CLINICAL STUDY PROTOCOL 
 
APIXABAN FOR THE TREATMENT OF VENOUS THROMBOEMBOLISM IN 
PATIENTS WITH CANCER: A PROSPECTIVE RANDOMIZED OPEN 
BLINDED END-POINT (PROBE) STUDY - THE CARAVAGGIO STUDY 
 
 
IND/EUDRACT NUMBER 2016-003093-40 
 
Principal investigator & study chairman: 
Giancarlo Agnelli, MD 
Internal and Cardiovascular Medicine and Stroke Unit 
University of Perugia, Perugia, Italy 
giancarlo.agnelli@unipg.it 
 
Promoter: 
Fondazione FADOI Italian Federation of Hospital Internists) 
Via F. Grossi Gondi, 49 
Rome, Italy 
 
Protocol number: FADOI 03.2016 
FINAL Version 3.0: May 22nd, 2018 
 
 
 
 

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SYNOPSIS 
EudraCT/IND 
Number:
2016-003093-40 
Protocol Number: 
FADOI 03.2016 
Investigational 
Product: 
Apixaban (BMS-562247-01) 
Study Title: 
Apixaban for the treatment of venous thromboembolism in patients 
with cancer: a prospective randomized open blinded end-point 
(PROBE) study - the Caravaggio study
Short Title: 
Apixaban for venous thromboembolism (VTE) in cancer patients 
Study Phase: 
Phase IIIb trial 
Indication Under 
Investigation: 
Apixaban for venous thromboembolism in cancer patients  
Study Aim: 
The aim of this study is to assess whether oral apixaban is non-inferior 
to the subcutaneous low molecular weight (LMWH) dalteparin for the 
treatment of newly diagnosed proximal deep vein thrombosis (DVT) 
and/or pulmonary embolism (PE) in patients with cancer.
Study Design: 
This is a multinational, prospective, randomized, open-label, blinded 
end-point (PROBE), non-inferiority study.  
Study population: 
Inclusion criteria:  
  
1) Consecutive patients with a newly diagnosed, objectively 
confirmed: 
• symptomatic or unsuspected, proximal lower-limb DVT or 
• symptomatic PE or  
• unsuspected PE in a segmental or more proximal 
pulmonary artery. 
    
2) Any type of cancer (other than basal-cell or squamous-cell 
carcinoma of the skin, primary brain tumor or known intracerebral 
metastases and acute leukemia) that meets at least one of the 
following: 
• Active cancer defined as diagnosis of cancer within six 
months before the study inclusion, or receiving treatment 
for cancer at the time of inclusion or any treatment for 

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cancer during 6 months prior to randomization, or recurrent 
locally advanced or metastatic cancer. 
• Cancer diagnosed within 2 years before the study inclusion 
(history of cancer). 
    
3) Signed and dated informed consent, available before the start of any 
specific trial procedure. 
  
Exclusion criteria:  
 
Patients are ineligible for the study in case of: 
 
1) age <18 years  
 
2) ECOG Performance Status III or IV; 
 
3) life expectancy of less than 6 months; 
 
related to anticoagulant treatment: 
 
4) administration of therapeutic doses of LMWH, fondaparinux, or 
unfractionated heparin (UFH) for more than 72 hours before 
randomization; 
 
5) 3 or more doses of a vitamin K antagonist before randomization; 
 
6)  thrombectomy, vena cava filter insertion, or thrombolysis used to 
manage the index episode; 
 
7) indication for anticoagulant treatment for a disease other than the 
index VTE episode;  
 
8) concomitant use of strong inhibitors or inducers of both 
cytochrome P-450 3A4 and P-Glycoprotein (see Appendix 1); 
 
 
related to bleeding risk: 
 
9) concomitant thienopyridine therapy (clopidogrel, prasugrel, or 
ticagrelor) or aspirin over 165 mg daily or dual antiplatelet 
therapy; 
 
10) 
 active 
bleeding 
or 
high 
risk 
of 
bleeding 
contraindicating anticoagulant treatment  
 
11) 
recent (in the last 1 month prior to randomization) brain, 
spinal or ophthalmic surgery;

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12) hemoglobin level lower than 8 g/dL (5.0 mmol/L) or platelet 
count 
<75x109/L 
or 
history 
of 
heparin-induced 
thrombocytopenia; 
 
13) creatinine clearance < 30 ml /min based on the Cockcroft Gault 
equation; 
  
14) acute hepatitis, chronic active hepatitis, liver cirrhosis; or an 
alanine aminotransferase level 3 times or more and/or bilirubin 
level 2 times or more the upper limit of the normal range; 
 
15) uncontrolled hypertension (systolic BP> 180 mm Hg or diastolic 
BP > 100 mm Hg despite antihypertensive treatment); 
 
standard criteria: 
 
16) bacterial endocarditis; 
 
17) hypersensitivity to the study drugs or to any of their excipients; 
 
18) Patient’s participation in other pharmaco-therapeutic program 
with an experimental therapy that is known to affect the 
coagulation system. 
 
19) women of childbearing potential (WOCBP) who do not practice 
a medically accepted highly effective contraception during the 
trial and one month beyond. Highly effective contraception 
methods are: 
a. combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation 
b. progestogen-only hormonal contraception associated with 
inhibition of ovulation 
c. intrauterine device (IUD) 
d. intrauterine hormone-releasing system (IUS) 
e. bilateral tubal occlusion 
f. vasectomized partner 
g. sexual abstinence; 
 
20) pregnancy or breast feeding 
 
21) any condition that, as judged by the investigator, would place the 
subject at increased risk of harm if he/she participated in the 
study. 

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Efficacy Study 
Outcomes: 
Primary efficacy outcome: objectively confirmed recurrent VTE 
occurring during the study treatment period, that means the 
composite of: 
 
• proximal DVT of the lower limbs (symptomatic or 
unsuspected)  
 
• DVT of the upper limb (symptomatic)   
 
• PE (symptomatic or unsuspected)  
 
Secondary efficacy outcomes:  
• the individual components of the primary efficacy 
outcome; 
 
•  symptomatic recurrence of VTE; 
•  all cause death; 
 
•  the composite of primary efficacy outcome plus major 
bleeding; 
 
•  the composite of primary efficacy outcome plus major 
bleeding plus all cause death; 
 
•  the composite of primary efficacy outcome plus all cause 
death; 
 
•  any major cardiovascular event, fatal or non-fatal (including
acute myocardial infarction or ischemic stroke); 
 
•  all venous thromboembolic events (including splanchnic
vein thrombosis and cerebral vein thrombosis); 
 
•  Quality of life (QoL) according to Anti-Clot Treatment
Scale (ACTS) (see Appendix 2) 
 
 
Safety Study 
Outcomes: 
 
Primary safety outcome is major bleeding, defined (as per ISTH 
guidelines), as acute clinically overt bleeding associated with one or 
more of the following: 
• decrease in hemoglobin of 2 g/dl (1.2 mmol/L) or more; 
• transfusion of 2 or more units of packed red blood cells; 

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• bleeding that occurs in at least one critical site [intracranial, 
intra-spinal, intraocular (within the corpus of the eye; thus, a 
conjunctival bleed is not an intraocular bleed), pericardial, intra-
articular, intramuscular with compartment syndrome, or 
retroperitoneal];  
• bleeding that is fatal;  
• bleeding that necessitates acute surgical intervention 
 
Secondary safety outcomes include: 
• Clinically relevant non-major bleeding event defined as acute 
 clinically overt bleeding that does not meet the criteria for major  
 and consists of: 
• 
any bleeding compromising hemodynamics; 
• 
spontaneous hematoma larger than 25 cm2, or 100 cm2 if 
there was a traumatic cause;  
• 
intramuscular hematoma documented by ultrasonography; 
• 
epistaxis or gingival bleeding requiring tamponade or other 
medical intervention or bleeding from venipuncture for >5 
minutes; 
• 
hematuria that was macroscopic and was spontaneous or 
lasted for more than 24 hours after invasive procedures;  
• 
hemoptysis, hematemesis or spontaneous rectal bleeding  
requiring endoscopy or other medical intervention; 
• 
or any other bleeding considered to have clinical 
consequences for a patient such as medical intervention, 
the need for unscheduled contact (visit or telephone call) 
with a physician, or temporary cessation of a study drug, 
or associated with pain or impairment of activities of daily 
life. 
 
• Clinically relevant bleeding defined as the composite of major and 
clinically relevant non-major bleeding 
 
• Permanent early discontinuation of study drug due to safety reasons.
Study treatments and 
visits: 
Patients will be randomized on a 1:1 basis (permuted blocks of four) to 
receive either apixaban or dalteparin in an open-label fashion. 
 
Apixaban group: orally administered, at the dose of 10 mg bid for 7 days,
followed by 5 mg bid (total period of treatment: six months) 
 
Dalteparin group: subcutaneously administered, at a dose of 200 IU/kg 
SC o.i.d for 1 month. Thereafter, dalteparin will be administered at a

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dose of 150 IU/kg o.i.d. for 5 months (total period of treatment: six 
months). The maximum daily dose allowed for dalteparin is 18,000IU. 
 
Randomization will be centralized and stratified by: 
 
1) symptomatic vs. unsuspected VTE 
2) active cancer vs. history of cancer 
 
Apixaban 5mg will be supplied by the Promoter as film-coated tablets.
 
Dalteparin will be supplied by the Promoter as single-use pre-filled 
syringes. 
 
The study requires the following scheduled visits: at enrollment, at 4 
weeks, at 3 months, at 6 months, at the end of study treatment whenever 
it occurs, and at 7 months from randomization. 
Additional visits will be performed if new symptoms and/or signs of 
VTE or major bleeding develop. A clinical examination and objective 
tests will be performed if the patient develops symptoms or signs 
suggestive of recurrent VTE.
Planned Sample Size: 
The study has been designed to test the hypothesis that apixaban would 
be non-inferior to dalteparin with respect to the primary efficacy 
outcome. 
The criteria for non-inferiority require that the upper limit of the two-
sided 95% confidence interval of the Hazard ratio is below the pre-
specified margin of 2.00. 
With the use of an estimated incidence of the primary efficacy outcome 
of 7% at 6 months with dalteparin and an upper non-inferiority margin 
of 2.00 for the hazard ratio, we calculated that we would need to enroll 
934 completer patients for the study to have 80% power to show the non-
inferiority of apixaban, at a one-sided alpha level of 0.025. This sample 
will be increased to 1168 patients to account for up to 20% lost in total 
patient-years. This estimate is consistent with a drop-out rate of 40% 
assuming patients discontinued uniformly during the follow-up (mean 
discontinuation time equal to 3 months) 
Statistical Analysis: 
Analysis of the Primary Study Outcome 
 
The primary efficacy data set will consist of all randomized subjects 
who received at least one dose of the study drugs (modified intent-to 
treat population) with a non-missing primary outcome. Subjects will 
be categorized to the group to which they were assigned at 
randomization, regardless of the treatment actually received.

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The secondary efficacy data sets will consist of a) all randomized 
subjects (intent-to treat population) and b) the per-protocol population 
(defined in the SAP). 
The safety data set will consist of all treated subjects (randomized 
subjects who received at least one dose of study drug).  
The primary efficacy variable, i.e. the time from randomization to the 
first recurrent thromboembolic event, will be analyzed after adjusting 
estimates for the competing risk of death unrelated to VTE.  
The evaluation of the primary objective will be done by considering 
the time from randomization to the first recurrent thromboembolic 
event (event of interest) or to the occurrence of death unrelated to 
VTE (nuisance/competing event) or to the last follow-up if neither a 
recurrent thromboembolic event nor a competing event occurred 
within the intended 6-month study treatment period (censored time).   
 
Analyses of the primary efficacy endpoint will be performed using the 
modified intent-to-treat principle, the intent-to treat principle and the 
per protocol principle. The modified intent-to-treat and the intent-to-
treat analyses of the primary endpoint will include endpoints that occur 
at any time from randomization until the end of their originally 
intended treatment period regardless of whether subjects were 
receiving study medication.  
A per protocol analysis of the primary endpoint will include endpoints 
that occur in patients who complete the study fully compliant with the 
protocol and without any major violation or deviation (defined in the 
SAP). 
For the secondary efficacy outcomes, analyses will be performed 
using the primary efficacy data set.  
 
The apixaban-to-comparator Hazard Ratio adjusted for the competing 
risk of death unrelated to VTE will be computed with associated two-
sided 95% Confidence Interval by resorting to the Fine & Gray 
regression model (Fine and Gray, 1999) using treatment group and 
center as dummy covariates.  
Apixaban will be considered non-inferior to the comparator dalteparin 
if the upper two-sided 95% confidence limit of hazard ratio is < 2.00. 
Superiority of apixaban vs. dalteparin will be tested as a secondary 
analysis of the primary endpoint, only after non-inferiority has been 
demonstrated for the experimental treatment group (apixaban) relative 
to the standard treatment group (dalteparin). According to 
CPMP/EWP/482/99 document entitled: "Points to consider on 
switching between superiority and non-inferiority", switching the 
apixaban vs. dalteparin contrast from the non-inferiority objective to 
the superiority objective is feasible because the trial is properly 
designed in accordance to the strict requirements of a non-inferiority 
trial.  

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For the purpose of safety analyses, subjects will be categorized to the 
group to which they were assigned at randomization unless incorrect 
study treatment was received throughout the study, in which case the 
subject will be categorized according to the treatment received. 
All safety analyses will be conducted on the safety population. The 
term “treatment period” refers to the period between the first 
administration of study drug and 48 hours after the last administration 
of study drug. This period will be the basis for the summaries of 
safety.
Study Sites and 
Location: 
Approximately 140 study sites in 11 countries are planned to enroll 
patients in this study 
 

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TABLE OF CONTENTS 
 
SYNOPSIS ....................................................................................................................... 2 
1. LIST OF ABBREVIATIONS .................................................................................... 12 
2. 
INTRODUCTION .................................................................................................. 14 
3. AIM OF THE STUDY ............................................................................................... 15 
4. EXPERIMENTAL DESIGN ...................................................................................... 15 
4.1 Design of the study ............................................................................................... 15 
4.2 Study population ................................................................................................... 15 
4.2.1. Inclusion Criteria .......................................................................................... 15 
4.2.2. Exclusion Criteria ......................................................................................... 16 
5. STUDY OUTCOMES ................................................................................................ 18 
5.1 Efficacy outcomes ................................................................................................ 18 
5.2. Safety outcomes ................................................................................................... 20 
6. STUDY PROCEDURES ............................................................................................ 21 
6.1   Subject information and informed consent ......................................................... 21 
6.2   Randomization .................................................................................................... 21 
6.3. Visits schedule and follow-up ............................................................................. 22 
6.4. Observations and measurements ......................................................................... 23 
6.5. Withdrawn/discontinuation of Subjects from Therapy ....................................... 26 
6.5.1. Reasons for Withdrawal/Early Discontinuation ........................................... 26 
6.5.2 Withdrawal of Consent from Study Participation ....................................... 289 
6.5.3  Subjects Lost to Follow-Up .......................................................................... 29 
6.6. Withdrawal Procedures........................................................................................ 29 
7. DATA QUALITY CONTROL AND ASSURANCE ................................................ 30 
7.1.   Requirements for investigational sites and staff ................................................ 30 
7.2.   Direct access to Source Data/Documents ........................................................ 301 
7.3. Investigator Site File and archiving ..................................................................... 31 
7.4. Monitoring ......................................................................................................... 312 
8. STUDY ORGANIZATION ..................................................................................... 323 
8.1 Study Committees............................................................................................... 323 
9. ADVERSE EVENTS ................................................................................................. 33 
9.1     Definition .......................................................................................................... 33 
9.1.1     Serious Adverse Events ........................................................................... 334 
9.1.2      Adverse Events of Special Interest (AESI) ............................................ 355 
9.1.3 
Bleeding Outcomes ................................................................................ 355 
9.1.4      Adverse Event Severity .......................................................................... 356 
9.1.5  Clarification of the difference in meaning between "serious" and "severe"366 
9.1.6  Adverse Drug Reaction (ADR) .................................................................. 366 
9.1.7  Serious Adverse Drug Reaction (SADR) ..................................................... 36 

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9.1.8  Suspected Unexpected Serious Adverse Reaction (SUSAR) ....................... 36 
9.1.9  Causality Assessment ................................................................................. 367 
9.1.10  Action Taken Regarding the Study Product ............................................. 377 
9.2     Collection, Reporting and Documentation of AEs ........................................... 37 
9.2.1    Serious Adverse Event Collection and Reporting for Investigators ......... 389 
9.2.2  Notifying Regulatory Authorities, Investigators, and IRB/IEC ................... 40 
9.3    Laboratory Test Result Abnormalities ............................................................ 401 
9.4     Pregnancy ....................................................................................................... 411 
9.5     Overdose ......................................................................................................... 412 
10.  STATISTICAL CONSIDERATIONS .................................................................. 422 
10.1. Sample Size / Power Determinations .............................................................. 422 
10.2. Rationale for the event rates in the two treatment arms .................................. 423 
10.3. Rationale for Non-inferiority margin (delta) choice ........................................ 444 
10.4. Analysis Populations ....................................................................................... 445 
10.5. Demographic and Baseline Data ..................................................................... 455 
10.6. Efficacy Analyses .............................................................................................. 45 
10.7. Safety Analyses ................................................................................................. 48 
10.8. Subgroup Analyses .......................................................................................... 489 
10.9. Detailed Statistical Analysis Plan .................................................................... 499 
11. FEASIBILITY ........................................................................................................ 499 
12. INSURANCE ......................................................................................................... 499 
13. PROMOTER ............................................................................................................ 49 
14. REFERENCES ......................................................................................................... 50 
15. APPENDICES .......................................................................................................... 53 
Appendix 1 – Concomitant medications .................................................................... 53 
Appendix 2 – Quality of Life assessment / Anti-Clot Treatment Scale (ACTS) ....... 57 
Appendix 3 – Schedule of assessments ...................................................................... 59 
Appendix 4 – Protocol Signature Page (protocol writers) .......................................... 61 
Appendix 5 – Protocol Signature Page (principal Investigator) ................................. 62 
  
 
 
 
 
 

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1. LIST OF ABBREVIATIONS 
ACTS 
Anti-Clot Treatment Scale 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ADR 
Adverse Drug Reaction 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Transaminase 
AST 
Aspartate Transaminase  
CEC 
Clinical Event Adjudication Committee 
CK-MB 
Creatine Kinase- MB 
CrCL 
Creatinine Clearance 
CRO 
Contract Research Organization 
DVT 
Deep Vein Thrombosis 
DSMB 
Data Safety Monitoring Board 
DSUR 
Development Safety Update Report 
ECOG 
Eastern Cooperative Oncology Group (Performance scale) 
eCRF 
electronic Case Report Form 
FADOI 
Italian Federation of Hospital Internists 
FAS 
Full Analysis Set  
ICH-GCP 
International Conference on Harmonization – Good Clinical Practice 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
ISTH 
International Society on Thrombosis and Hemostasis 
IWRS 
Interactive Web-based Randomization System 
LMWH 
Low molecular weight 
MedDRA 
Medical Dictionary for Regulatory Activities 
PE 
Pulmonary Embolism 
PIN 
Personal Identification Number 

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PROBE 
Prospective Randomized Open Blinded End-Point  
RBM 
Risk Based Monitoring  
QoL 
Quality of Life 
SAE 
Serious Adverse Event 
SASR 
Serious Adverse Drug Reaction 
SAP 
Statistical Analysis Plan 
SC 
Steering Committee 
SDEA 
Safety Data Exchange Agreement 
SOCs 
System Organ Classes 
SMS 
Short Message Service 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
UFH 
Unfractioned Heparin 
ULN 
Upper Limit of Normal 
VTE 
Venous Thromboembolism 
WBC 
White Blood Cells 
WHO 
World Health Organization 
WOCBP 
Women of childbearing potential 
 

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2. INTRODUCTION 
Venous thromboembolism (VTE) is a common clinical event in patients with cancer. The 
development of VTE is presumed to be due to the production of pro-coagulant molecules 
by cancer cells and to the pro-coagulant effect of cancer cells spread into the circulation. It 
should be taken into account that cancer surgery and chemotherapy are associated with a 
substantial increase in the risk of VTE. Moreover, the risk for recurrence both while on 
anticoagulant therapy and after its discontinuation was shown to be particularly high in 
patients with cancer associated VTE (1). The risk for bleeding complications on 
anticoagulant treatment is also higher in cancer patients than in non-cancer patients such 
making crucial the balance between benefit and risk (1).  
The CLOT study, performed more than 15 years ago, showed that in patients with cancer-
associated VTE, anticoagulant treatment with the low-molecular-weight heparin (LMWH) 
dalteparin was more effective and similarly safe compared to vitamin K antagonists (2). 
These results were confirmed in studies with a more limited number of patients (3). Thus, 
current guidelines recommend the use of LMWH, given subcutaneously, for the acute and 
long-term treatment of VTE in cancer patients (4-5). In the recently published CATCH 
study in cancer patients, the LMWH tinzaparin was associated with a non-significant 35% 
risk reduction in recurrence of VTE compared to vitamin K antagonists (6). In the CATCH 
study, there were no differences in the incidence of major bleeding between the two 
treatment groups.  
Due to the high risk for recurrence, cancer patients who experience VTE are candidates to 
indefinite treatment duration or to prolong treatment until cancer is completely cured (4-
5).  The availability of an oral anticoagulant treatment, as effective and safe as LMWH, 
would be a substantial advantage for patients with cancer who develop VTE. During the 
last years, new oral anticoagulants given at fixed doses without the need of laboratory 
monitoring and dose adjustment were shown to be as effective as and probably safer than 
vitamin K antagonists for the treatment of VTE (7). The results of phase III clinical trials 
led to their approval for the acute and long-term treatment of VTE. Unfortunately, the 
clinical trials on the treatment of VTE with the new oral anticoagulants included only a 
limited number of patients with cancer. Thus, whether the results obtained in the general 
population of patients with VTE also attain to cancer patients remains undefined.  
Subgroup analyses on the efficacy and safety profile of the anti-Xa oral agent apixaban for 
the treatment of VTE in cancer patients have been recently reported (8-11). In these patients, 
with all the limitations related to a subgroup analysis, apixaban appeared to be at least as 
effective as LMWH given with and followed by vitamin K antagonists (10). A recent meta-
analysis in cancer patients showed a similar efficacy and safety profile of new oral 
anticoagulants in comparison with LMWH given with and followed by vitamin K 
antagonists for the treatment of VTE (12). 
 
 

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3. AIM OF THE STUDY 
The aim of this study is to assess whether apixaban is non-inferior to the LMWH dalteparin 
for the treatment of newly diagnosed proximal deep vein thrombosis (DVT) and/or 
pulmonary embolism (PE) in patients with cancer. 
4. EXPERIMENTAL DESIGN 
4.1 Design of the study 
This is a multinational, prospective, randomized, open-label, blinded end-point (PROBE), 
non-inferiority study comparing apixaban to the LMWH dalteparin in the treatment of VTE 
in patients with cancer.  
4.2 Study population 
Patients with cancer and newly objectively diagnosed proximal lower-limb DVT, or PE 
or both will be eligible for the study. 
Patients will be included after screening for inclusion and exclusion criteria (see sections 
4.2.1 and 4.2.2) and the signature of the informed consent form. Patients will be encouraged 
to ask any questions regarding the study aims and procedures, to be answered 
straightforwardly by one of the Investigators. 
 
4.2.1. Inclusion Criteria  
Consecutive patients with: 
 
1)  a newly diagnosed, objectively confirmed: 
• 
symptomatic or unsuspected, proximal lower-limb DVT or 
• 
symptomatic PE or  
• 
unsuspected PE in a segmental or more proximal pulmonary artery. 
 
Unsuspected VTE is defined as DVT or PE detected by imaging testing performed not to 
confirm the suspicion of VTE but for other reasons (e.g. cancer diagnosis or staging). 
 
The diagnosis of DVT requires the evidence of one or more filling defects at compression 
ultrasonography, venography, CT venography or MR venography involving at least the 
popliteal vein or more proximal veins.  
 
The diagnosis of PE requires one or more among: 
- 
 an intraluminal filling defect at CT pulmonary angiography; 
- 
 an intraluminal filling defect, or a new sudden cut-off of vessels more than 2.5 mm 
in diameter at pulmonary angiogram; 

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- 
a perfusion defect of at least 75% of a segment with a local normal ventilation result 
(high probability) on ventilation/perfusion lung scan (VQ scan); 
- 
in unsuspected PE, there must be one or more filling defect in segmental or more-
proximal arteries at chest CT pulmonary angiography.  
 
 
2)  Any type of cancer (other than basal-cell or squamous-cell carcinoma of the skin, 
primary brain tumor or intracerebral metastases and acute leukemia) that meets at 
least one of the following: 
• 
Active cancer defined as diagnosis of cancer within six months before the 
study inclusion, or receiving treatment for cancer at the time of inclusion or 
any treatment for cancer during 6 months prior to randomization, or recurrent 
locally advanced or metastatic cancer. 
• 
Cancer diagnosed within 2 years before the study inclusion (history of cancer). 
 
 
3) signed and dated informed consent, available before the start of any specific trial 
procedure. 
 
4.2.2. Exclusion Criteria 
Patients are ineligible for the study in case of: 
 
1)  age <18 years  
 
2)  ECOG Performance Status III or IV; 
 
3)  life expectancy of less than 6 months; 
 
 
related to anticoagulant treatment: 
 
4) administration of therapeutic doses of LMWH, fondaparinux, or unfractionated 
heparin (UFH) for more than 72 hours before randomization; 
 
5) 3 or more doses of a vitamin K antagonist before randomization; 
 
6) thrombectomy, vena cava filter insertion, or thrombolysis used to manage the index 
episode; 
 
7) indication for anticoagulant treatment for a disease other than the index VTE;  
 
8) concomitant use of strong inhibitors or inducers of both cytochrome P-450 3A4 and 
P-Glycoprotein (see Appendix 1); 
 
related to bleeding risk: 

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9) concomitant thienopyridine therapy (clopidogrel, prasugrel, or ticagrelor) or aspirin 
over 165 mg daily or dual antiplatelet therapy; 
 
10) active bleeding or a high risk of bleeding contraindicating anticoagulant treatment;  
 
11) recent (in the last 1 month prior to randomization) brain, spinal or ophthalmic surgery;  
 
12) hemoglobin level lower than 8 g/dL (5.0 mmol/L) or platelet count < 75x109/L or 
history of heparin induced thrombocytopenia; 
 
13) creatinine clearance < 30 ml /min based on the Cockcroft Gault equation; 
  
14) acute hepatitis, chronic active hepatitis, liver cirrhosis; or an alanine aminotransferase 
level 3 times or more and/or bilirubin level 2 times or more the upper limit of the 
normal range; 
 
15)  uncontrolled hypertension (systolic BP> 180 mm Hg or diastolic BP > 100 mm Hg 
despite antihypertensive treatment); 
 
standard criteria: 
 
16) bacterial endocarditis; 
 
17) hypersensitivity to the study drugs or to any of their excipients; 
 
18) Patient’s participation in other pharmaco-therapeutic program with an experimental 
therapy that is known to affect the coagulation system. 
 
19) Women of childbearing potential (WOCBP) who do not practice a medically accepted 
highly effective contraception during the trial and one month beyond. Highly effective 
contraception methods are: 
a. combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation 
b. progestogen-only hormonal contraception associated with inhibition of ovulation 
c. intrauterine device (IUD) 
d. intrauterine hormone-releasing system (IUS) 
e. bilateral tubal occlusion 
f. vasectomized partner 
g. sexual abstinence; 
 
20) pregnancy, or breast feeding; 

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21) any condition that as judged by the investigator would place the subject at increased 
risk of harm if he/she participated in the study. 
    
Patient has the right to refuse further participation in the study at any time and without 
providing any reasons. Patients may be withdrawn from the study at any time at the 
discretion of the investigator; however, in this case, the reason should be fully documented. 
 
5. STUDY OUTCOMES 
5.1 Efficacy outcomes 
The primary efficacy outcome is objectively confirmed recurrent proximal DVT or PE 
occurring during the study treatment period, that means the composite of: 
 
a)  
ipsilateral proximal DVT of the lower limbs (symptomatic or unsuspected):  
A recurrent proximal DVT must be distinguished from the original thrombus by comparing 
serial imaging modalities (compression ultrasonography, venography, CT venography, or 
MR venography). In order to be classified as a recurrent event, there must be one or more 
new filling defect evident on the second imaging test not evident on the original images, 
or an interval imaging test clearly showing thrombus resolution; only in symptomatic 
patients, if the venous segment was non-compressible at randomization, a substantial 
increase (4 mm or more) in diameter of the thrombus during full compression.  
 
b) 
 contralateral proximal DVT of the lower limbs (symptomatic or 
unsuspected):  
In order to be classified as a recurrent event, there must be one or more new filling defects 
at compression ultrasonography, venography, CT venography, or MR venography. 
Unsuspected thrombus must be evident on the second imaging test and not evident on the 
original images.  
 
c)  
DVT of the upper limbs (symptomatic)  
 
In order to be classified as a recurrent event, there must be one or more new filling defects 
at compression ultrasonography, venography, CT venography, or MR venography.  
 
d) pulmonary embolism (symptomatic or unsuspected):  
 
-  Symptoms of PE with one of the following findings: 
• 
 a new intraluminal filling defect at CT pulmonary angiography; 
• 
 a new intraluminal filling defect, or an extension of an existing defect, or a 
new sudden cut-off of vessels more than 2.5 mm in diameter at pulmonary angiogram; 

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• 
 a new perfusion defect of at least 75% of a segment with a local normal 
ventilation result (high probability) on ventilation/perfusion lung scan (VQ scan); 
• 
 inconclusive CT pulmonary angiography, pulmonary angiography, or VQ 
scan evidence of a new or recurrent PE with demonstration of a new or recurrent DVT 
in the lower extremities by compression ultrasonography or venography. 
 
- Fatal PE defined as PE based on objective diagnostic testing before death or autopsy; 
death where PE is the most probable cause of a sudden and unexplained death according 
to central adjudication. 
 
- In unsuspected PE, in order to be classified as a recurrent event, there must be one or 
more new filling defect in segmental or more-proximal arteries at CT pulmonary 
angiography evident on the second study not appreciated on previous images or an interval 
study clearly showing emboli resolution. 
 
The secondary efficacy outcomes of the study are: 
• 
the individual components of the primary efficacy outcome; 
• 
symptomatic recurrence of VTE; 
• 
all cause death; 
• 
the composite of primary efficacy outcome plus major bleeding; 
• 
the composite of primary efficacy outcome plus major bleeding plus all cause death; 
• 
the composite of primary efficacy outcome plus all cause death; 
• 
any major cardiovascular event, fatal or not fatal (including acute myocardial 
infarction1 or ischemic stroke2); 
• 
all venous thromboembolic events (including splanchnic vein thrombosis and cerebral 
vein thrombosis both objectively assessed); 
• 
Quality of Life (QoL), assessed by means of the Anti-Clot Treatment Scale (ACTS) 
(see Appendix 2). 
                                                 
1 An acute myocardial infarction requires the presence of at least 2 out of the 3 following conditions: 
- an appropriate clinical situation suggestive of a myocardial infarction (eg, abnormal history, physical 
examination or new ECG changes) 
- elevation of CK-MB or Troponin T or I ≥ 2 x ULN; if no CK-MB or troponin values are available, a total CK 
≥2x ULN 
- new, significant (≥0.04 seconds) Q waves in ≥ 2 contiguous leads. 
2 An acute stroke is defined as a new, focal neurological deficit of sudden onset, lasting at least 24 hours, 
that is not due to a readily identifiable non-vascular cause (i.e., brain tumor, trauma). All strokes during 
the study will be assessed by imaging or autopsy and classified as primary hemorrhagic, non-
hemorrhagic, infarction with hemorrhagic conversion, or unknown, as defined by the American College of 
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5.2. Safety outcomes 
The primary safety outcome is major bleeding, defined (as per ISTH guidelines), as acute 
clinically overt bleeding associated with one or more of the following: 
 
• 
 a decrease in hemoglobin of 2 g/dl or more; 
• 
 a transfusion of 2 or more units of packed red blood cells; 
• 
 bleeding that occurs in at least one of the following critical sites 
[intracranial, intra-spinal, intraocular (within the corpus of the eye; thus, a 
conjunctival bleed is not an intraocular bleed), pericardial, intra-articular, 
intramuscular with compartment syndrome, or retroperitoneal];  
• 
 bleeding that is fatal (defined as a bleeding event that the independent 
Clinical Event Adjudication Committee determined was the primary cause of 
death or contributed directly to death);  
• 
 bleeding that necessitates surgical intervention. 
 
Secondary safety outcomes include: 
• 
Clinically relevant non-major bleeding event defined as acute clinically overt 
bleeding that does not meet the criteria for major and consists of: 
• 
 any bleeding compromising hemodynamics; 
• 
 spontaneous hematoma larger than 25 cm2, or 100 cm2 if there was a traumatic 
cause;  
• 
 intramuscular hematoma documented by ultrasonography; 
• 
 epistaxis or gingival bleeding requiring tamponade or other medical 
intervention or bleeding from venipuncture for >5 minutes; 
• 
 hematuria that was macroscopic and was spontaneous or lasted for more than 
24 hours after invasive procedures;  
• 
  hemoptysis, hematemesis or spontaneous rectal bleeding requiring 
endoscopy or other medical intervention; 
• 
 or any other bleeding considered to have clinical consequences for a patient 
such as medical intervention, the need for unscheduled contact (visit or 
telephone call) with a physician, or temporary cessation of a study drug, or 
associated with pain or impairment of activities of daily life. 
 
• 
Clinically relevant bleeding defined as the composite of major and clinically relevant 
non-major bleeding 
• 
 Permanent early discontinuation of study drug due to safety reasons. 
 

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6. STUDY PROCEDURES 
6.1   Subject information and informed consent  
Before being admitted to the clinical trial, the subject must consent to participate after 
being fully informed about the nature, scope, and possible consequences of the clinical 
trial. 
The documents must be in a language understandable to the subject and must specify who 
informed the subject. 
A copy of the signed informed consent document must be given to the subject. The 
original signed consent document will be retained by the investigator. 
The investigator will not undertake any measures specifically required only for the 
clinical trial until valid consent has been obtained. 
Moreover, the investigator, by the means of the specific template approved by his local 
EC, should inform the subject’s primary physician about the subject’s participation in the 
trial - provided the subject agrees to the primary physician being informed. 
After reading the informed consent document, the subject must give consent in writing. 
The subject's consent must be confirmed by the personally dated signature of the subject 
and by the personally dated signature of the study doctor conducting the informed consent 
discussions. 
Additionally, in this study, for those centers interested in using it, the Informed Consent 
administration could be conducted through an electronically managed procedure. In 
details the study investigator by the means of a tablet, will open the appropriate Informed 
Consent form and provide it to the patient for reading and understanding.  The study 
investigator will then require an automated generated PIN code that will be directly 
received by the patient on his/her own personal mobile phone via SMS. Once the patient 
will have carefully read and/or listened the informed consent text, he/she will sign it 
electronically by entering the PIN code. 
A PDF copy of the electronically signed Informed Consent will be generated for 
investigator and patient’s filing. 
No personal patient’s contact details (like mobile phone number) will be recorded in the 
study data-base. 
 
6.2   Randomization 
Patients will be randomized to receive: 
Apixaban group: orally administered, at the dose of 10 mg bid for 7 days, followed by 5 
mg bid;  
Dalteparin group: subcutaneously administered, at a dose of 200 IU/kg SC o.i.d for 1 
month. Thereafter, dalteparin will be administered at a dose of 150 IU/kg o.i.d. for 5 
months. The maximum daily dose allowed for dalteparin is 18,000IU.  
Enrolled patients will receive the study drug for 6 months.  

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Figure. Study design. 
Patients will be randomized on a 1:1 basis (permuted blocks of four) to receive either 
Apixaban or Dalteparin in an open-label fashion. 
 
Randomization will be centralized and stratified by: 
1)  symptomatic vs. unsuspected VTE 
2)  active cancer vs. history of cancer 
The maximum proportion of patients entering the study with unsuspected VTE is set at 
20% of the overall study population. After this proportion is reached, randomization of 
patients with unsuspected VTE will not be allowed.   
The maximum proportion of patients entering the study with history of cancer is set at 20% 
of the overall study population. After this proportion is reached, randomization of patients 
with history of cancer will not be allowed.   
 
6.3. Visits schedule and follow-up  
The study requires the following scheduled visits: at enrolment, at 4 weeks, at 3 months, at 
6 months, at the end of study treatment whenever it occurs, and at 7 months from 
randomization.  
Additional visits will be performed if new symptoms and/or signs of VTE or major 
bleeding develop. A clinical examination and objective tests will be performed if the 
patient develops symptoms or signs suggestive of recurrent VTE.  
 
Confirmed DVT 
without 
symptomatic PE 
R
Apixaban
Apixaban
10 mg bid
5 mg bid
Dalteparin 200 IU/kg od        Dalteparin 150 IU/kg od 
30 day 
observation 
period 
     Day 1                Day 7    
 Day 28                 
Confirmed PE 
with or without 
symptomatic DVT
< 72 hrs*
* Maximum time allowed between diagnosis and randomization

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6.4. Observations and measurements 
The investigator or a delegate will complete an electronic Case Report Form (eCRF) to 
document the study data. 
During the screening visit the investigator or delegate will obtain: 
 
• 
written informed consent; 
• 
relevant medical history; 
• 
information on symptoms of VTE, site and confirmatory tests;  
• 
data on type, site and staging of cancer 
• 
date of cancer diagnosis 
• 
data on type and timing of cancer treatment (chemotherapy, radiotherapy, surgery)  
• 
physical exams and measure of vital signs (e.g. body weight, blood pressure, heart 
rate) 
• 
pregnancy test (WOCBP only) 
• 
the following local laboratory results: 
Serum chemistry 
- 
 Total bilirubin (direct and indirect) 
- 
 Alanine transaminase (ALT) 
- 
 Aspartate transaminase (AST) 
- 
 Alkaline phosphatase (ALP) 
- 
 Serum creatinine 
- 
 CrCL 
Hematology and platelet count 
- 
 Hematocrit  
- 
 White blood cell (WBC) count  
- 
 Hemoglobin  
- 
 Platelet count 
- 
 INR 
- 
 partial prothrombin time;  
• 
concomitant medication use (within 30 days prior to screening visit); 
• 
screening on inclusion/exclusion criteria 
 
Investigators should provide documentation of the index VTE event (qualifying imaging) 
and cancer (histology reports) during the period that extends from screening period up to 
two weeks after randomization.  
 
Procedures to be performed at enrollment include: 
 
• 
determine if subject continues to meet inclusion/exclusion criteria; 

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• 
 randomize the subject to study medication through the Interactive Web-based 
Randomization System (IWRS) embedded in the eCRF  
• 
 dispense study treatment. 
 
At 4-week and 3-month follow-up visits: 
The investigator or delegate will: 
 
• 
assess study outcomes (i.e. suspected recurrent VTE, bleeding), including subjects 
who have discontinued study treatment. For subjects who have discontinued study 
treatment, telephone query of health status (alive, occurrence of efficacy and safety 
endpoints and AEs/SAEs) is allowed. Subjects who have new symptoms should 
undergo further assessment as clinically appropriate, preferably at the study site 
whenever feasible. 
• 
check the following local laboratory results: 
Serum chemistry 
- 
 Total bilirubin (direct and indirect) 
- 
 Alanine transaminase (ALT) 
- 
 Aspartate transaminase (AST) 
- 
 Alkaline phosphatase (ALP) 
- 
 Serum creatinine 
- 
 CrCL 
Hematology and platelet count 
- 
 Hematocrit  
- 
 White blood cell (WBC) count  
- 
 Hemoglobin  
- 
 Platelet count; 
 
• 
collect study medication dispensed at previous visit;  
• 
assess study medication use; 
• 
measure the body weight; 
• 
dispense study medication assigned for the current visit; 
• 
assess concomitant medication use; 
• 
for patients with study outcomes investigators should provide documentation for the 
recurrent VTE event (qualifying imaging) within four weeks. 
 
At 6-month follow-up visit or end of study treatment: 
 
The investigator or delegate will: 
 
• 
assess study outcomes (i.e. suspected recurrent VTE, bleeding), including subjects 
who have discontinued study treatment. For subjects who have discontinued study 

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treatment, telephone query of health status (alive, occurrence of efficacy and safety 
endpoints and AEs/SAEs) is allowed. Subjects who have new symptoms should 
undergo further assessment as clinically appropriate, preferably at the study site 
whenever feasible. 
• 
check the following local laboratory results: 
 
Serum chemistry 
- 
 Total bilirubin (direct and indirect) 
- 
 Alanine transaminase (ALT) 
- 
 Aspartate transaminase (AST) 
- 
 Alkaline phosphatase (ALP) 
- 
 Serum creatinine 
- 
 CrCL 
Hematology and platelet count 
- 
 Hematocrit  
- 
 White blood cell (WBC) count  
- 
 Hemoglobin  
- 
 Platelet count; 
 
• 
collect study medication dispensed at previous visit;  
• 
assess study medication use; 
• 
assess concomitant medication use; 
• 
for patients with study outcomes investigators should provide documentation for the 
recurrent VTE event (qualifying imaging) within four weeks. 
• 
assess Quality of Life (QoL) by means of the Anti-Clot Treatment Scale (ACTS) at 
the end of the study treatment. 
 
At 7-month after randomization: 
The investigator or delegate will: 
 
• 
assess for AE/SAE(s) 
• 
for patients with study outcomes investigators should provide documentation for the 
recurrent VTE event (qualifying imaging) within four weeks. 
• 
assess efficacy and safety (i.e. recurrent VTE, major bleeding), including subjects who 
have discontinued study treatment. Query of health status (alive, occurrence of 
efficacy endpoints and SAEs) and current anticoagulant treatment by telephone is 
allowed.  
 
Unscheduled Visit: 
An unscheduled visit may occur during the study treatment period, at any time the 
Investigator considers it might be necessary. 

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The procedures and assessments performed during an unscheduled visit strictly depends 
by the reason why such visit occurs. 
 
6.5. Withdrawn/discontinuation of Subjects from Therapy 
 
6.5.1. Reasons for Withdrawal/Early Discontinuation 
 
A subject may discontinue or interrupt study drug for a number of reasons including, but 
not limited to, those listed below: 
 
• 
 Permanent Discontinuation 
- Death; 
- Withdrawal of consent as defined in Section 6.5.2; 
- Pregnancy  
- Lost to follow-up as defined in Section 6.5.3 (every attempt will be made by the 
investigator not to have subjects "lost to follow-up"); 
- CrCL decrease to < 30 mL/min, confirmed by repeat testing at least 1 week later 
or need for kidney dialysis; 
- Investigator judgment due to: 
SAE or other safety concern e.g., 
- Major life-threatening bleeding 
- Onset of clinical jaundice or other overt signs of liver toxicity 
- Unfavorable benefit-to-risk evaluation for continuing anticoagulant 
treatment 
- Termination of all or part of the study by the DSMB acting in concert with the 
Promoter. 
 
• 
 Temporary Discontinuation 
Temporary discontinuations of apixaban and dalteparin for 3 or more consecutive days will 
be recorded in the eCRF.  
Potential reasons may include: 
- Short-term use of prohibited concomitant medications (see Appendix 1); 
- Surgical procedures; 
- Any medical condition where continuing study drug may expose the subject to an  
increased hazard; 
- New onset of elevated liver enzymes in the absence of a known cause: 
- ALT > 8 × ULN 
- AST or ALT > 5 x ULN for more than two weeks 
- ALT or AST > 3 x ULN, but not reaching the limits in the above criteria, in 
combination with clinical symptoms suggestive of hepatitis 
- ALT or AST > 3 x ULN with TBL > 2 x ULN 
- New onset or deteriorating renal failure <30ml/h 

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- Platelet count < 50x109/L (50,000/mm3) 
 
In patients receiving Dalteparin who experience platelet counts between 50,000 and 
100,000/mm3, the daily dose of Dalteparin should not be discontinued but reduced until 
the platelet count recovers to ≥100,000/mm3. Please refer to your local product package 
insert for dosing reduction guidance for this patient population. 
 
During a study drug discontinuation, a subject can be placed on antithrombotic therapy per 
local guidelines and the investigator's discretion.  
Post-randomization changes (other than CrCL decreased to < 30 mL/min or need for kidney 
dialysis) in health status related to study exclusion criteria should not automatically lead to 
study drug interruption or discontinuation unless continuing study drug places the subject 
at undue hazard as determined by the investigator. Such situations should be handled on a 
case-by-case basis. It is strongly recommended that the investigator consults with the 
dedicated Medical Support Line (telephone number: +39 0236725581) if a subject has a 
post randomization change in health status that is associated with an exclusion criterion. 
Also, a decision to stop prematurely the overall recruitment in the study and/or intake of 
study drug can be taken by the Executive Committee/Promoter following advice on safety 
aspects of the study by the DSMB. The IECs/IRBs will be informed of this decision. The 
DSMB stopping guidelines will be defined prior to the start of the study. The Promoter has 
the right to close the study and the right to close a center, at any time, although this should 
occur only after consultation between involved parties and the Executive Committee. The 
IECs/IRBs must be informed. Should the site be closed prematurely, all study materials 
(except documentation that has to remain stored at site) must be returned to the Promoter. 
The investigator will retain all other documents until notification by Promoter for 
destruction. 
If the subject is withdrawn due to an adverse event, the investigator will follow the subject 
until the adverse event has resolved or stabilized. 
 
 
Emergency Surgery 
If an urgent surgical intervention is needed, anticoagulant therapy should be discontinued 
and the surgery should be deferred, if possible, until at least 12 hours and ideally 24 hours 
after the last administration of anticoagulant therapy. There is no reversal agent for 
apixaban. Protamine can be used to (partially) reverse the effect of dalteparin. Depending 
upon the clinical situation and local availability, the use of coagulation factors or other 
measures can be considered in case of the recent intake of apixaban prior to the surgical 
procedure. It is recommended to consult the Medical Support Line (telephone number: +39 
0236725581) in case of urgent surgery. 
 
Therapeutic Management of Subjects for Planned Interventions  

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It is advised to withhold apixaban at least 48 hours prior to elective surgery or invasive 
procedures with a high risk of bleeding. This includes interventions for which the 
probability of clinically significant bleeding cannot be excluded or for which the risk of 
bleeding would be unacceptable.  
Apixaban should be discontinued at least 24 hours prior to elective surgery or invasive 
procedures with a low risk of bleeding. This includes interventions for which any bleeding 
that occurs is expected to be minimal, non-critical in its location or easily controlled.  
Apixaban should be restarted after the invasive procedure or surgical intervention as soon 
as possible provided the clinical situation allows and adequate hemostasis has been 
established. 
Dalteparin should be withhold at least 24 hours prior to the planned intervention. 
Dalteparin can be resumed upon complete hemostasis and after the assessment of the 
bleeding risk, i.e., after 6 to 24 hours for most minor procedures and after 2-3 days for most 
surgical procedures that carry a bleeding risk.  
Antithrombotic therapy other than the study drug can be initiated, e.g., a (prophylactic) 
dose of LMWH, according to the institutional best practice, until re-initiating dosing of the 
study drug is considered to be appropriate. 
It is recommended to consult the Medical Support Line (telephone number: +39 
0236725581) in case of any further questions on the management of subjects who need a 
planned intervention. 
 
Therapeutic Management of Subjects in Other Critical Situations 
Other critical situations could be admission to hospital for acute medical illness or active 
periods of chemotherapy. In these circumstances, gastrointestinal disorders might preclude 
intake of oral therapy with apixaban and bridging to LMWH is allowed. In case of doubt 
it is recommended to contact the Medical Support Line (telephone number: +39 
0236725581). 
 
6.5.2 Withdrawal of Consent from Study Participation 
In accordance with the Declaration of Helsinki and other applicable regulations, a subject 
has the right to withdraw consent from study participation at any time and for any reason 
without prejudice to his or her future medical care by the physician or at the institution. 
However, it is important to distinguish between withdrawal of consent with regards to 
continuing on study medication (but continuing to be followed on study) versus withdrawal 
of consent with regards to discontinuing the study all together (i.e., withdrawal of consent 
with regards to continuing on study medication and any further study follow-up). 
Only subjects who refuse all 4 of the following methods of follow-up will be considered to 
have withdrawn consent from study participation: 
- Participation in the trial follow-up visits per protocol, either in clinic or by 
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- Contact by trial personnel even if only by telephone;  
- Permission for trial personnel to contact an alternative person (e.g., family member, 
spouse, partner, legal representative, physician, the anticoagulation clinic, or 
another healthcare provider) even if only by telephone; 
- Permission for trial personnel to access and review their medical information from 
alternative sources (e.g., doctor’s notes, hospital records). 
If the subject refuses all 4 of the above methods of follow-up, the investigator should 
personally speak to the subject to ensure the subject understands all the potential methods 
of follow-up. If the subject continues to refuse all potential methods of follow-up, the 
Investigator will document this as a withdrawal of consent in the medical record. 
All subjects should be followed for the full duration of the trial using any or all of the above 
methods, unless there is written documentation by the investigator of the subject's 
withdrawal of consent to ALL of the above methods of follow-up. 
The site will complete and report the observations as thoroughly as possible up to the date 
of consent withdrawal and including the date of the final dose of study drug. The reason(s) 
for limited follow-up/data collection will be clearly documented in the medical record and 
eCRF. 
Public databases and subject finder services may be used to determine subject status and 
to locate potential lost to follow-up patients. 
6.5.3 Subjects Lost to Follow-Up 
The investigator will make every effort not to have any subjects lost to follow-up. If a 
subject is potentially lost to follow-up (e.g., missed study visits, unable to be contacted by 
phone), the investigator will make every effort to contact the subject before the subject is 
declared lost to follow-up.  
 
6.6. Withdrawal Procedures 
Follow-Up of Subjects with Study Drug Discontinuation 
The investigator may contact the dedicated Medical Support Line (telephone number: +39 
0236725581) in case of any questions regarding how to handle a study drug discontinuation 
or interruption. 
All randomized subjects, including those who temporarily interrupted or discontinued 
study drug, will be followed for a 7-month period after randomization, except when the 
study is truncated as noted in Section 6.5.1. 
In case of premature discontinuation of treatment, study outcomes can be collected by 
telephone contact until 7 months after the first dose of study drug. If the subject has an on-
site visit at any time after study drug discontinuation, it is expected that a clinical status 
will be obtained along with any laboratory assessments deemed appropriate by the 
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If the subject and investigator agree that study drug can be resumed without increased 
hazard to the subject, study medication may be resumed at any time, regardless of the 
duration of study drug interruption. 
Any subject who temporarily interrupts or discontinues study drug due to confirmed liver 
enzyme abnormalities or jaundice in the absence of a known cause, must have an evaluation 
to determine the cause of the event. Evaluation may include the following depending on 
the clinical situation: 
- Abdominal ultrasound; 
- Hepatitis A, B, C, and E screening (anti-HAV IgM, HbsAg, anti-HCV plus viral 
titer, and evaluation for Hep E), Antinuclear antibody (ANA) and anti-SmAb, 
Cytomegalovirus (CMV), Epstein Barr virus (EBV); 
- Additional evaluations as deemed appropriate by the investigator to exclude other 
causes of liver enzyme and bilirubin elevations. 
Follow-up of liver enzymes and bilirubin (total and direct) should be performed on a 
weekly basis until the values return to baseline. 
All laboratory results, including local laboratory reference ranges are to be recorded in the 
eCRF. 
All clinically significant hepatic enzyme abnormalities and/or hepatic events are to be 
documented in the eCRF and prompt submission of the adjudication dossier should also 
occur when indicated.  
 
7. DATA QUALITY CONTROL AND ASSURANCE 
7.1.   Requirements for investigational sites and staff    
The investigator should be able to demonstrate (e.g., based on retrospective data) a 
potential for recruiting the required number of suitable subjects within the agreed 
recruitment period.    
The investigator should have sufficient time to properly conduct and complete the trial 
within the agreed trial period.    
The investigator should have available an adequate number of qualified staff trained on 
protocol procedures and adequate facilities for the foreseen duration of the trial to conduct 
the trial properly and safely.   
 
7.2. Direct access to Source Data/Documents  
Original data, also known as source data/records, are those data elements that represent 
the first recording of study data. Original data contain all the information that is necessary 
for the reconstruction and evaluation of the study. Examples of original data are 1) 
subject's information used in a clinical trial whether collected on paper or electronically 

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at the time of the subject's visit, 2) certified copies of original records, 3) observations, 
and 4) laboratory data from clinical laboratories. Clinical investigators maintain control 
over source data from inception to the end of the regulatory retention period. The 
investigator must permit access to these data during Exom Site Monitor’s monitoring 
visits, audits, ECs reviews, and regulatory inspections.  
In addition to original records maintained by the clinical site as part of their standard 
practices of patient care, this study requires that certified electronic copies of: 
a) the index VTE event (qualifying imaging) and of cancer diagnosis (histology reports) 
during the period that extends from screening period up to two weeks after randomization  
b) all suspected outcome events as soon as they occur. 
to be uploaded by the investigator into a dedicated eSource repository, independent from 
the study database, access to which is controlled by the qualified investigative site staff.  
Only authorized Exom Group users can get access to these eSource documents and 
provide in an anonymized format, to the Clinical Event Adjudication Committee (CEC) 
for review and classification, those documents related to clinical events and diagnoses.   
 
 
7.3. Investigator Site File and archiving   
The investigator will be provided with an access to an electronic investigator site file 
(eISF) at the start of the trial. The investigator will archive all trial data and relevant 
correspondence in the ISF. The ISF, all source data and all documents will be kept filed 
according to the requirements of the ICH-GCP guidelines not only during the study period 
but also after its termination.     
It is responsibility of the investigator to ensure that the subject-identification sheets and 
the originally signed informed consent forms are properly stored for at least 15 years 
beyond the end of the clinical trial.   
 
 
 
 
 
7.4. Monitoring   
Monitoring procedures will be followed, in order to comply with Good Clinical Practice 
(GCP) guidelines. Three different types of monitoring activities will be performed by the 
appointed CRO: on site, remote and central monitoring. 
Each center will be visited at regular intervals by a CRO Site Monitor to ensure 
compliance with the study protocol, GCP and legal aspects. This will include on-site 
checking of the electronic case report forms (eCRF) for completeness and clarity, cross-
checking with source documents, and clarification of administrative matters.  

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The Site Monitor will ensure that the investigator will maintain a list of sub-investigators 
and other appropriately qualified persons to whom he or she has delegated significant 
trial-related duties (personnel log). During the on-site monitoring visits, the Site Monitor 
will review the entries into the eCRF for completeness and correctness and verify the 
entries on the basis of the source documents. The presence of correct informed consents 
will be checked for every subject.      
The investigator must allow the Site Monitor to look at all relevant documents and must 
provide support at all times to the Site Monitor.   
Moreover, remote monitoring by means of phone calls between investigators and Site 
Monitors will be done.   
The risk for the occurrence of quality and safety issues will be regularly and centrally 
monitored through the use of a “Risk Based Monitoring & Management” (RBM) 
platform. For each of following six risk categories: 1) site management quality, 2) data 
quality, 3) data timeliness, 4) source documents verification, 5) milestone delay, 6) 
subject safety, study specific risk indicators and related scores will be defined and closely 
and centrally monitored during the entire study period. This will allow prompt and 
targeted remedial actions. 
 
8. STUDY ORGANIZATION 
The study will be coordinated by the Internal and Cardiovascular Medicine and Stroke Unit 
of the University of Perugia, Italy and by the Research Department of FADOI Foundation. 
FADOI Foundation is the Promoter of the study, and owner of the data. 
The study will be approved by appropriate Competent Authorities as well as Central IRB, 
if available, or by Local Ethical Committee of each participating institution. All patients 
will sign an informed consent form after the explanation of the protocol and the purpose of 
the study.  
 
 
 
8.1 Study Committees  
Steering committee 
The Steering Committee will consist of the Principal Investigator of the study, the National 
Coordinators and members of FADOI Foundation and University of Perugia, Italy. This 
Committee will have the final responsibility for the study design and oversight, as well as 
data verification and analyses. All the members of the steering committee will have access 
to the study data, contribute to the interpretation of the results, approve the final version of 
the manuscript, and make the decision to submit the manuscript for publication, and vouch 
for the accuracy and completeness of the data reported and the fidelity of the article to the 

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study protocol. A Writing Committee composed by Steering Committee members will 
write the first version of the manuscript.  
 
Clinical Event Adjudication Committee 
An independent committee, whose members will be unaware of treatment allocation, will 
adjudicate all suspected outcome events and the qualifying diagnosis, the anatomical extent 
of the initial DVT or PE.  
 
 
Data Safety Monitoring Board (DSMB) 
An independent Data and Safety Monitoring Board will periodically review the study 
outcomes having all information available concerning treatment allocation. A DSMB 
charter will be provided to the board members before the start of the study. 
 
 
9. ADVERSE EVENTS 
9.1     Definition 
An Adverse Event (AE) is defined as any new untoward medical occurrence or 
worsening of a preexisting medical condition in a clinical investigation subject 
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 
study drug, whether or not considered related to the study drug. 
The causal relationship to study drug is determined by a physician and should be used to 
assess all adverse events (AE). The causal 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). 
 
9.1.1     Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: 

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•  results in death; 
•  is life-threatening (defined as an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it was more severe);  
•  requires hospitalization or causes prolongation of existing hospitalization (see 
NOTE below); 
•  results in persistent or significant disability/incapacity; 
•  is a congenital anomaly/birth defect;  
•  is an important medical event (defined as a medical event(s) that may not be 
immediately life-threatening or result in death or hospitalization but, based upon 
appropriate medical and scientific judgment, may jeopardize the subject or may 
require intervention [e.g., medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are 
not limited to, intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or seizures that do not result in hospitalization. 
Potential drug induced liver injury (DILI) is also considered an important medical 
event.  
 
Although not always serious adverse events by regulatory definition, the following events 
must be handled as SAEs: pregnancy, overdose, newly diagnosed cancer, exposure (to 
fetus) during pregnancy, exposure (to infant) during lactation, and paternal exposure, 
overdose, abuse, misuse, off-label use, occupational exposure, medication error and 
potential medication error, suspected transmission of an infectious agent (e.g., any 
organism, virus or infectious particle pathogenic or non-pathogenic, via the medicinal 
product). 
 
NOTE: 
The following hospitalizations are not considered SAEs in FADOI Foundation clinical 
studies: 
• a visit to the emergency room or other hospital department of less than 24-hour 
duration, 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 (e.g., 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 (e.g., lack of housing, 

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economic inadequacy, caregiver respite, family circumstances, administrative 
reason); 
• admission for administration of anticancer therapy in the absence of any other 
SAEs (applies to protocols involving cancer patients). 
 
9.1.2      Adverse Events of Special Interest (AESI) 
In this study, the following adverse events of special interest (AESI) are to be reported to 
CRO/Promoter immediately, 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. 
 
9.1.3 Bleeding Outcomes 
All major bleedings defined as: 
• 
a decrease in hemoglobin of 2 g/dl or more; 
• 
a transfusion of 2 or more units of packed red blood cells; 
• 
bleeding that occurs in at least one of the following critical sites    [intracranial, 
intra-spinal, intraocular (within the corpus of the eye; thus, a conjunctival 
bleed is not an intraocular bleed), pericardial, intra-articular, intramuscular 
with compartment syndrome, or retroperitoneal];  
• 
bleeding that is fatal (defined as a bleeding event that the independent Clinical 
Event Adjudication Committee determined was the primary cause of death or 
contributed directly to death);  
• 
bleeding that necessitates surgical intervention 
 
and all clinically relevant non-major bleedings must be reported and will be reviewed 
and classified by the CEC.   
 
9.1.4      Adverse Event Severity 
The following categories and definitions of intensity as determined by a physician should 
be used for all FADOI Foundation clinical study AEs: 
•  Mild (Grade 1)  Event which is well tolerated by the patient and does not 
interfere with normal daily activities; 
•  Moderate (Grade 2)  Event which results in discomfort for the patient and 
impairs his/her normal activities; 
•  Severe (Grade 3)  Medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling and 
resulting in substantial impairment of normal activities of the subject; 

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•  Very Severe (Grade 4)  Life-threatening consequences; urgent intervention 
indicated.  
 
9.1.5 Clarification of the difference in meaning between "serious" and "severe" 
The terms “serious” and “severe” are not synonymous but are often used interchangeably. 
The term ‘severe’ is often used to describe the intensity (severity) of a specific event; the 
event itself, however, may be of relatively minor significance (such as severe headache). 
This is not the same as “serious”, which is based on subject/event outcome or action 
criteria usually associated with events that pose a threat to a subject’s life or functioning. 
Seriousness (not severity) serves as a guide for defining regulatory reporting obligations. 
9.1.6 Adverse Drug Reaction (ADR)  
An adverse drug reaction is any noxious and unintended response to an investigational 
medicinal product (the causal relationship between the medicinal product and the adverse 
event is at least a reasonable possibility). 
9.1.7 Serious Adverse Drug Reaction (SADR) 
If there is a causal relationship between a serious adverse event and trial medication, then 
the event is called serious adverse drug reaction (SADR). 
9.1.8 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A SUSAR is a serious adverse reaction which is unexpected. An unexpected serious 
adverse reaction is any adverse reaction, the nature or severity of which is not consistent 
with the current Summary of Product Characteristics. 
 
9.1.9 Causality Assessment 
The following categories and definitions of causal relationship to investigational product 
as determined by a physician should be used for all FADOI Foundation clinical study 
AEs: 
• Certain: There is a reasonable causal relationship between the investigational product 
and the AE. The event responds to withdrawal of investigational product (dechallenge), 
and recurs with rechallenge when clinically feasible. 
• Probable: There is a reasonable causal relationship between the investigational product 
and the AE. The event responds to dechallenge. Rechallenge is not required. 
• Possible: There is reasonable causal relationship between the investigational product 
and the AE. Dechallenge information is lacking or unclear. 

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• Not likely: There is a temporal relationship to investigational product administration, 
but there is not a reasonable causal relationship between the investigational product and 
the AE. 
• Not related: There is not a temporal relationship to investigational product 
administration (too early, or late, or investigational product not taken), or there is a 
reasonable causal relationship between non-investigational product, concurrent disease, 
or circumstance and the AE. 
 
9.1.10 Action Taken Regarding the Study Product 
•  1 = Dose Not Changed  No change in study drug dosage was made; 
•  2 = Drug Withdrawn  The study product was permanently stopped; 
•  3 = Drug Interrupted  The study product was temporarily stopped. 
 
 
9.2     Collection, Reporting and Documentation of AEs  
This study will follow a targeted approach to AE and SAE collection and reporting.  
All AEs occurring after the subject signs the ICF and through Month 6 or the global EOT 
date, whichever occurs first, whether observed by the Investigator or reported by the 
subject, will be recorded on the Adverse Events section of the eCRF if they fulfill one of 
the following criteria:  
1) meet seriousness criteria;  
2) result in interruption or discontinuation of the assigned study drug;  
3) meet criteria as a study outcome; or  
4) an event of special interest. 
All laboratory, vital sign, or electrocardiogram (ECG) values should be evaluated by the 
Investigator regarding clinical significance. Isolated abnormal laboratory results or vital 
sign findings or ECG findings should be reported as AEs if they are symptomatic, result 
in study drug discontinuation, require corrective treatment, or are otherwise defined as an 
AE of Special Interest (AESI).  
Clinically significant abnormal laboratory findings associated with the subject’s cancer 
or other pre-existing conditions will not be reported as AEs or SAEs unless judged by the 
Investigator as more severe than expected for the subject’s condition and meet the criteria 
for targeted AE and SAE reporting.  
Medical conditions (including laboratory values/vital signs that are out of range) that were 
diagnosed or known to exist prior to informed consent will be recorded as part of medical 
history.  
All SAEs occurring after informed consent for study participation has been obtained, 
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are to be reported according to the procedures for Serious Adverse Event Reporting-
Procedure for Investigators. 
A preplanned (prior to signing the Informed Consent Form) procedure or treatment 
requiring hospitalization for pre-existing conditions which do not worsen in severity 
should not be reported as SAEs.  
For deaths, the underlying or immediate cause of death should always be reported as an 
SAE. When a subject dies from disease progression of pre-existing cancer with no other 
immediate causes, “disease progression” should be reported as an SAE. In addition, any 
serious, untoward event that may occur subsequent to the reporting period that the 
Investigator assesses as related to study drug should also be reported and managed as an 
SAE. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. In order to prevent reporting bias, subjects should 
not be questioned regarding the specific occurrence of one or more AEs. If known, the 
diagnosis of the underlying illness or disorder should be recorded, rather than its 
individual symptoms. The following information should be captured for all AEs: onset, 
duration, intensity, seriousness, relationship to investigational product, action taken and 
treatment required and outcome. If treatment for the AE was administered, it should be 
recorded on the appropriate eCRF page.  
The Investigator’s assessment must be clearly documented in the site’s source 
documentation with the Investigator’s signature. 
Investigator should follow subjects with AEs until the event has resolved or the condition 
has stabilized.  
In case of unresolved AEs including significant abnormal laboratory values at the end of 
study assessment, these events will be followed up until resolution or until they become 
clinically not relevant. 
The investigator shall supply the Promoter and Ethics Committee with any additional 
requested information, notably for reported deaths of subjects. Possible additional 
information on the AE collected/identified during the study will be reported on the eCRF.  
 
 
9.2.1 Serious Adverse Event Collection and Reporting for Investigators 
Following the subject’s or the legal representative’s written consent to participate in the 
study, all AEs, SAEs, AESIs, bleeding outcomes and study outcomes will be captured in 
the eCRF. 
Study outcomes are clinically anticipated events and will be periodically reviewed by the 
DSMB to ensure prompt identification of any clinically concerning safety issues. Study 
outcomes (suspected recurrent DVT or PE, major bleedings, clinically relevant non-major 
bleedings, MI, stroke, and venous thrombotic events at other locations) will be exempted 
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(SUSARs) to regulatory authorities, Investigators, IECs, and IRBs. All SAEs resulting in 
death, regardless of whether they are waived endpoint events, will be captured in the 
Promoter’s global safety database. 
The following types of events whether related or not related to study drug, must be 
reported within 24 hours of the Investigator’s awareness, to the Contract Research 
Organization Exom Group: 
•   SAEs  
•   AESIs  
•   Severe Hypersensitivity (Steven-Johnson Syndrome, Toxic Epidermal 
Necrolysis)  
•   Overdose 
•   Pregnancies  
As a preferred method, all SAEs and Liver Enzyme abnormalities/dysfunction events, 
must be recorded on the eSAE Report Form of the eCRF; while pregnancies on the 
ePregnancy Surveillance Form.  
The paper SAE/Pregnancy Surveillance forms are only intended as a back-up option when 
the eCRF system is not accessible. In this case, the original paper forms are to remain on 
site and copies are to be transmitted via email or confirmed facsimile (fax) transmission 
to: 
SAE Email Address: caravaggio.phv@exomgroup.com 
A SAE Telephone Contact Number +39 06 9480 1010 is also available, in case of 
additional support. 
The initial SAE Report should be as complete as possible including the essential details 
of subject’s identification (Subject ID), the serious adverse event (medical term, 
diagnosis), the trial medication and the assessment of the causal relationship between the 
event and the trial medication. The SAE report must be reviewed and signed by the 
investigator. 
The investigator should provide related additional information on the clinical course and 
the outcome of each SAE as soon as possible (eSAE Follow-up Report). 
 
 
9.2.2 Notifying Regulatory Authorities, Investigators, and IRB/IEC   
The study Promoter FADOI Foundation will ensure that all legal reporting requirements 
are met, according to local laws and regulations. Further, according to GCP, the study 
Promoter is responsible for the continuous safety evaluation of the product(s) investigated 
in the clinical trial. 
FADOI Foundation and/or Exom Group will notify the Competent Authorities and Ethics 
Committees of all SAEs that are suspected (certainly, probably, or possibly related to the 
investigational product) and unexpected (i.e., not previously described in the Summary 
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Reaction (SUSAR, see Section 9.1.8). Notification of these events will be in the form of 
an Expedited Safety Report (ESR), to be delivered as soon as possible but not later than 
15 calendar days if the event is non-fatal and 7 calendar days if it was fatal. 
All investigators will be informed, too. 
Other important findings which may be reported by the study Promoter as an ESR 
include:  
• increased frequency of a clinically significant expected SAE;  
• a SAE considered associated with study procedures that could modify the conduct 
of the study;  
• important safety recommendations from the study Data and Safety Monitoring 
Board (DSMB, see below), or  
• Promoter’s decision to end or temporarily halt a clinical study for safety reasons. 
 
During the clinical trial duration, the Promoter will submit to the Ethics Committee(s) 
and to the Competent Authorities, once a year, a study specific Development Safety 
Update Report (DSUR) including a list of all serious adverse reactions. 
 
FADOI Foundation is also responsible for reporting of safety information to the 
marketing authorization holders (Bristol-Meyers Squibb and Pfizer) of the two 
investigational products.  
 
Work flow, procedures and responsibility concerning SAE management will be described 
in a separate document named SDEA (Safety Data Exchange Agreement). 
 
All potential study outcomes (e.g. DVT, PE) and potentially major or clinically relevant 
bleedings will be adjudicated by the Clinical Event Adjudication Committee (CEC). 
The result of the adjudication will be a classification of the event as  
- 
primary efficacy or safety endpoint or  
- 
no outcome.  
The classification will be recorded in the study database. 
 
A Data Safety Monitoring Board (DSMB) will be established for this study, and 
responsible for monitoring of safety and efficacy during the course of the clinical trial. 
The recommendations of the DSMB with respect to the study conduct will be presented 
to the study’s Steering Committee (SC), in writing. 
 
9.3 Laboratory Test Result Abnormalities 
Only laboratory test result abnormalities that meet one of the following criteria:   
•  clinically significant or meets the definition of a SAE 
•  requires the subject to have study drug omitted or discontinued   

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•  requires the subject to receive specific corrective therapy  
should be recorded in the AE section of the study eCRF and reported immediately (within 
24 hours of the Investigator’s awareness) as any SAE (see Section 9.2.1) by the means of 
the eSAE Report Form. 
It is expected that wherever possible, the clinical rather than laboratory term would be 
used by the reporting investigator (e.g., anemia versus low hemoglobin value). 
 
9.4 Pregnancy 
If, following initiation of the study drug, it is subsequently discovered that a study subject 
is pregnant or may have been pregnant at the time of study drug exposure, including 
during at least 5 half-lives after product administration, the investigator must immediately 
notify FADOI Foundation of this event and complete and forward a Pregnancy 
Surveillance Form to FADOI Foundation within 24 hours and in accordance with SAE 
reporting procedures. 
In most cases, the study drug will be permanently discontinued in an appropriate manner. 
In the rare event that the benefit of continuing study drug is thought to outweigh the risk, 
after consultation with FADOI Foundation, the pregnant subject may continue study drug 
after a thorough discussion of benefits and risk. 
Protocol-required procedures for study discontinuation and follow-up must be performed 
on the subject unless contraindicated by pregnancy (e.g., x-ray studies). Other appropriate 
pregnancy follow-up procedures should be considered if indicated. 
The Investigator should make every effort to follow the subject until completion of the 
pregnancy. If the outcome of the pregnancy meets the criteria for immediate classification 
as a SAE (i.e., post-partum complications, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly, including that in an aborted fetus), the Investigator should 
follow the procedures for reporting SAEs by the means of the ePregnancy Surveillance 
Form.  
Any pregnancy that occurs in a female partner of a male study participant should be 
reported to FADOI Foundation as well. Information on this pregnancy will be collected 
on the ePregnancy Surveillance Form. 
 
9.5 Overdose 
All occurrences of overdose must be reported as SAEs. 

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10.  STATISTICAL CONSIDERATIONS 
10.1. Sample Size / Power Determinations 
The study has been designed to test the hypothesis that apixaban would be non-inferior 
to dalteparin with respect to the primary efficacy outcome. 
The criteria for non-inferiority require that the upper limit of the two-sided 95% 
confidence interval of the Hazard ratio is below the pre-specified margin of 2.00. 
With the use of an estimated incidence of the primary efficacy outcome of 7% at 6 months 
with dalteparin and an upper non-inferiority margin of 2.00 for the hazard ratio, we 
calculated that we would need to enroll 934 completer patients for the study to have 80% 
power to show the non-inferiority of apixaban, at a one-sided alpha level of 0.025. This 
sample will be increased to 1168 patients to account for up to 20% lost in total patient-
years.  
This estimate is consistent with a drop-out rate of 40% assuming patients discontinued 
uniformly during the follow-up (mean discontinuation time equal to 3 months).    
 
   
 
 
 
 
 
 
 
 
 
10.2. Rationale for the event rates in the two treatment arms  
Recurrence rate for dalteparin treated arm 
An event rate of 7% has been chosen according to the findings of the CLOT and of the 
CATCH trials. 
Both studies used a prospective randomized open blinded end-point (PROBE) design, 
had warfarin as the comparator vs LMWH, the same definition for active cancer, the same 
inclusion criteria concerning initial thromboembolic events, and the same treatment 
duration (6 months). Unlike the CLOT trial, in which dalteparin was given at a reduced 
dose after the first month, tinzaparin was given at a full dose throughout the study period 
in the CATCH study. The primary composite efficacy outcome was symptomatic 
 
HR Non-inferiority margin 
 
1.75 
2.0 
2.25 
Event rate 
6% 
 
1090 
 
796 
 
Sample size 
(pts)
7% 
 
934 
1250 
683 
914 
8% 
1250 
817 
 
597 
 
 
80% 
80% 
90% 
80% 
90% 
 
Power 

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recurrent VTE in the CLOT trial and symptomatic recurrent VTE plus unsuspected VTE 
in the CATCH trial. 
Reported incidence rates of recurrent VTE with LMWH were slightly different between 
the two studies, being 8.0% with Dalteparin in the CLOT study and 7.2% with Tinzaparin 
in the context of the CATCH trial. The incidence of recurrent VTE was higher in patients 
receiving warfarin in the CLOT trial (15.8%) than in the CATCH trial (10.5%); a risk 
reduction for recurrent VTE with LMWH as compared with warfarin of 52% and 35% 
was reported in the two studies, respectively. The 6-month mortality was lower in 
CATCH compared with CLOT (32% vs 40%).   
The lower risk for recurrent VTE observed in the CATCH trial may reflect critical 
differences in patient populations between the two studies. The prevalence of risk factors 
for recurrent thrombosis was lower in the CATCH as compared to the CLOT population 
and in particular fewer patients had metastatic disease (55% in CATCH vs 67% in CLOT), 
an ECOG performance status of 2 (23% for CATCH vs 36% for CLOT); less patients in 
the CATCH study received anticancer therapy (53% vs 78%), and had a previous history 
of thrombosis (6% vs 11%) compared with CLOT study. Moreover, differences in 
primary tumor sites and associated anticancer treatments, and the 10-year time gap 
between the 2 trials (during which cancer treatments have evolved) might also have 
contributed to the different risk for recurrent VTE. 
From the timing context point of view, our patient population is presumed to be closer to 
that of the CATCH study (published in 2015) than to the CLOT study (published in 2003). 
So it is plausible that patients enrolled in the Caravaggio study will receive less 
thrombogenic anticancer chemotherapy and improved disease management, as well as 
they will have less frequently a metastatic disease, due to an earlier diagnosis (screening 
improvement), like in the CATCH trial. 
As a further support to our study hypothesis, the ONCENOX trial, published in 2006, 
compared Enoxaparin (1.0 mg/kg bid for 5 days + warfarin for 6 months) vs Enoxaparin 
(1.0 mg/kg bid for 5 days followed by Enoxaparin 1.0 mg/kg od) (low dose – LD) with 
Enoxaparin (1.5 mg/kg od (high dose - HD) for 6 months) (13). The study was small with 
limited statistical power, and recurrent VTE was only a secondary objective. However, 
the rate of this endpoint was 6.9% with the LD and 6.3% with the HD of enoxaparin, 
therefore comparable to that observed in the CATCH trial. 
 
Recurrence rate for apixaban treated arm 
In a post hoc analysis of the Amplify study, 169 patients (3.1%) had active cancer at 
baseline and 365 (6.8%) had a history of cancer without active cancer at baseline. Among 
patients with active cancer, recurrent VTE occurred in 3.7% and 6.4% of evaluable 
patients in the apixaban and enoxaparin/warfarin groups, respectively (relative risk 0.56, 
95% confidence interval 0.13-2.37). Among patients with a history of cancer, recurrent 
VTE occurred in 1.1% and 6.3% of evaluable patients in the apixaban and 
enoxaparin/warfarin groups, respectively (relative risk 0.17, 95% confidence interval 
0.04-0.78). Based on these figures, and taking into account that in the present study more 

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patients with active cancer will be included, it is expected that the recurrent VTE rate in 
the apixaban treated patients will not be higher than the 7-8% observed in the LMWH 
treated groups in CLOT and CATCH studies. 
 
10.3. Rationale for Non-inferiority margin (delta) choice 
The goal of this trial is to test a drug that could lead to the more convenient oral route of 
administration and a trend towards better safety than the currently recommended LMWH 
treatment for cancer patients with VTE (14), thus fulfilling a gap within this therapeutic 
indication. In this situation, the choice of a relatively “large” delta for efficacy might be 
accepted in exchange for the possible safety and compliance benefits, provided that a 
putative superiority to placebo is not left in doubt (EMEA/CPMP/EWP/2158/99 
Document. Guideline on the choice of non-inferiority margin. July 27, 2005). Based on 
these assumptions, the upper limit of the two-sided 95% confidence intervals of the 
Hazard ratio below the pre-specified margin of 2.00 planned for our study seems to us 
acceptable from a clinical and methodological point of view.  
Further, it’s worth reminding that the non-inferiority margins used in pivotal trials on 
VTE therapy with direct oral anticoagulants were the following: 
•  1.5 for HOKUSAI-VTE (Edoxaban) (15) 
•  1.8 for AMPLIFY (Apixaban) (16) 
•  2.0 for EINSTEIN DVT and EINSTEIN PE (Rivaroxaban) (17-18) 
•  2.75 for RECOVER I and II (Dabigatran) (19-20) 
 
All the above mentioned studies were considered valid by EMA and FDA for registration 
of direct oral anticoagulants for the indication “treatment of VTE”. 
 
10.4. Analysis Populations 
The Full Analysis Set (FAS) consists of all randomized patients.   
The primary efficacy data set will consist of all randomized subjects who received at least 
one dose of the study drugs (modified intent-to treat population). Subjects will be 
categorized to the group to which they were assigned at randomization, regardless of the 
treatment actually received. 
Secondary efficacy data sets will consist of a) all randomized subjects (intent-to treat 
population) and b) the per-protocol population. The per-protocol population will be 
defined in the SAP. 
The safety data set (as-treated) will consist of all treated subjects (randomized subjects 
who received at least one dose of study drug). For the purpose of safety analyses, subjects 
will be categorized to the group to which they were assigned at randomization unless 
incorrect study treatment was received throughout the study, in which case the subject 
will be categorized according to the treatment received. 

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A Per Protocol (PP) population will consist of all patients in the FAS population who 
complete the study fully compliant with the protocol and without any major violation / 
deviation. Patients in the PP population will be analyzed according to the treatment they 
actually received. Efficacy analyses based on PP population will be considered supportive.   
The Safety population will consist of all randomized patients with at least one 
documented administration of any study drug. It will be the basis for the analyses of safety. 
Patients in the Safety population will be analyzed according to the treatment they actually 
received. Of note, a statement that a patient experienced no adverse events also constitutes 
a safety assessment.   
10.5. Demographic and Baseline Data   
Demographic and baseline patient characteristics will be summarized by treatment group 
for all patients in the FAS. Continuous-scaled variables (e.g., age) will be summarized 
with means, medians, standard deviations, quartiles, and minimum and maximum values. 
Categorical variables (e.g., sex) will be summarized using patient counts and percentages. 
Baseline medical histories and pre-existing conditions will be summarized by treatment 
group based on mapping to system organ classes (SOCs) and preferred terms in the 
Medical Dictionary for Regulatory Activities (MedDRA). Medications taken after the 
informed consent form is signed and before randomization will be summarized by 
treatment group, based on mapping to drug classes and generic terms in the WHO Drug 
Dictionary. 
10.6. Efficacy Analyses   
Analysis of Primary Endpoint   
Analyses of the primary efficacy endpoint will be performed using the modified intent-
to-treat and the intent-to treat principle and the per protocol principle. The modified 
intent-to-treat and the intent-to-treat analyses of the primary endpoint will include 
endpoints that occur at any time from randomization until the end of their originally 
intended treatment period regardless of whether subjects were receiving study 
medication.  
The primary efficacy variable, i.e. the time from randomization to the first recurrent 
thromboembolic event, will be analyzed after adjusting estimates for the competing risk 
of death unrelated to VTE (21). The competing risk analysis will be performed using the 
SAS macro %PSHREG (22) while the probabilities of failure for the event of interest 
(first recurrent thromboembolic event) are displayed using cumulative incidence plots 
which do account for the competing risk (death unrelated to VTE). 
The null hypothesis to be tested will be that apixaban is inferior to dalteparin in the 
prevention of recurrent thromboembolic events during 6-month follow-up; i.e. H0 → 
E[HR] ≥ 2.00. 

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The alternative hypothesis will be that apixaban is non-inferior to dalteparin in the 
prevention of recurrent thromboembolic events during 6-month follow-up; i.e. Ha → 
E[HR] < 2.00. 
Where: E[HR] is the Expected (E) apixaban-to-comparator Hazard Ratio (HR), while 
2.00 is the prefixed non-inferiority threshold.    
The evaluation of the primary objective will be done by considering the time from 
randomization to the first recurrent thromboembolic event (event of interest) or to the 
occurrence of death unrelated to VTE (nuisance/competing event) or to the last follow-
up if neither a recurrent thromboembolic event nor a competing event occurred within the 
6-month follow-up (censored time). The apixaban-to-comparator Hazard Ratio adjusted 
for the competing risk of death unrelated to VTE will be computed with associated two-
sided 95% confidence interval by resorting to the Fine & Gray regression model (23) 
using treatment group and center as dummy covariates. Apixaban will be considered non-
inferior to the comparator dalteparin if the upper two-sided 95% confidence limit of 
Hazard ratio is < 2.00. 
Superiority of apixaban vs. dalteparin will be tested as a secondary analysis of the primary 
endpoint, only after non-inferiority has been demonstrated for the experimental treatment 
group (apixaban) relative to the conventional treatment group (dalteparin). According to 
CPMP/EWP/482/99 document entitled: "Points to consider on switching between 
superiority and non-inferiority", switching the apixaban vs. dalteparin contrast from the 
non-inferiority objective to the superiority objective is feasible because the trial is 
properly designed in accordance to the strict requirements of a non-inferiority trial.  
 
Analysis of Secondary Endpoints   
For the secondary efficacy endpoints, analyses will be performed using the primary 
efficacy data set. 
• The individual components of the primary efficacy outcome: The same competing risk 
model (23) defined above for the analysis of primary efficacy variable will be employed 
for the analysis of the time from randomization to the first recurrent event among those 
included in the primary efficacy outcome recurrent (see 4.1). The apixaban-to-comparator 
Hazard Ratio adjusted for the competing risk of death unrelated to VTE will be computed 
with associated two-sided 95% confidence interval. 
• Symptomatic recurrence of VTE: The same competing risk model (23) defined above 
for the analysis of primary efficacy variable will be employed for the analysis of the time 
from randomization to the first symptomatic recurrent thromboembolic event. The 
apixaban-to-comparator Hazard Ratio adjusted for the competing risk of death unrelated 
to VTE will be computed with associated two-sided 95% confidence interval. 
• Composite of primary efficacy outcome plus major bleeding: The same competing 
risk model (23) defined above for the analysis of primary efficacy variable will be 
employed for the analysis of the time from randomization to the composite of primary 

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efficacy outcome plus major bleeding. The apixaban-to-comparator Hazard Ratio 
adjusted for the competing risk of death unrelated to VTE or major bleeding will be 
computed with associated two-sided 95% confidence interval. 
• All cause of death: Event free survival will be estimated according to Kaplan-Meier 
and the event free survival in the two treatment groups will be compared by means of a 
Cox’s proportional hazard model with treatment group and center as dummy covariates. 
The apixaban-to-comparator Hazard Ratio will be computed with associated two-sided 
95% confidence interval. 
• Composite of primary efficacy outcome plus major bleeding plus all cause death: 
Event free survival will be estimated according to Kaplan-Meier and the event free 
survival in the two treatment groups will be compared by means of a Cox’s proportional 
hazard model with treatment group and center as dummy covariates. The apixaban-to-
comparator Hazard Ratio will be computed with associated two-sided 95% confidence 
interval. 
• Composite of primary efficacy outcome plus all cause death: Event free survival will 
be estimated according to Kaplan-Meier and the event free survival in the two treatment 
groups will be compared by means of a Cox’s proportional hazard model with treatment 
group and center as dummy covariates. The apixaban-to-comparator Hazard Ratio will 
be computed with associated two-sided 95% confidence interval. 
• Any fatal or not fatal cardiovascular event: The same competing risk model (23) 
defined above for the analysis of primary efficacy variable will be employed for the 
analysis of the time from randomization to the occurrence of any fatal or not fatal 
cardiovascular event. The apixaban-to-comparator Hazard Ratio adjusted for the 
competing risk of death unrelated to cardiovascular event will be computed with 
associated two-sided 95% confidence interval. 
• All venous thromboembolic events (including splanchnic vein thrombosis and 
cerebral vein thrombosis): The same competing risk model (23) defined above for the 
analysis of primary efficacy variable will be employed for the analysis of the time from 
randomization to thromboembolic events at sites other than DVT and PE. The apixaban-
to-comparator Hazard Ratio adjusted for the competing risk of death unrelated to venous 
thromboembolic events will be computed with associated two-sided 95% confidence 
interval. 
• Quality of life evaluation (ACTS Scale) (see Appendix 2): For the total score and  
for each of the subscales, a linear effects model will be estimated with treatment group 
and center as dummy fixed effects. Results will be reported as Least-Square Means 
together with associated two-tailed 95% CI and p-value. ITT Analyses will be performed 
with missing data imputed using conventional LOCF. 
 
Multiplicity   

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No adjustment for multiplicity is required for the primary efficacy analysis because it is 
focused on a single time point (6-month) at which only two treatments are being 
compared. 
 
Center-to-center variability 
Study center and treatment-by-center interactions are included in each of the analyses 
described above. To assess center-to-center variability, forest plots will be generated to 
display the results at each center.   
Due to the possibility of small numbers of patients at some study sites, some sites may be 
combined in order to bring the numbers of patients in each pooled site to at least 12. Upon 
completion of the study and prior to unblinding, study statisticians in consultation with 
the Steering Committee will determine the pooling based on enrolment numbers and 
geographical proximity.  
 
10.7. Safety Analyses   
The analysis of safety will be based on the Safety Population, comparing patients in the 
two randomized arms: apixaban vs. dalteparin. AEs will be mapped to system organ 
classes and preferred terms in MedDRA. Treatment emergent events, defined as those 
that start or worsen after the start of apixaban/dalteparin AEs, will be summarized by 
treatment group, system organ class, and preferred term, and also by event severity and 
by the event’s relationship to study treatment. At each level of summation, patients will 
be counted only once, under the greatest severity and strongest study-drug relationship 
(as reported by the investigator). Clinical laboratory data will be summarized for each 
treatment group at each measurement time point and for each patient’s final post-baseline 
measurement in the following ways: (1) with descriptive statistics (mean, standard 
deviation, median, and range) for each measurement time point; (2) with descriptive 
statistics for the change from baseline in the measurements at each post-baseline time 
point; and (3) with shift tables summarizing the frequencies of patients below, within, and 
above the normal ranges at each time point as compared with baseline. All clinical 
laboratory values collected during the study will be listed, with values outside the normal 
ranges flagged for clinical evaluation. Concomitant medications will be summarized by 
treatment group based on mapping to drug classes and generic terms in the WHO Drug 
Dictionary.   
10.8. Subgroup Analyses   
Pre-specified subgroup analyses will be planned and reported in the statistical analysis 
plan before the un-blinding of the study. 
Interim Analyses   

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No interim analysis is planned.  
10.9. Detailed Statistical Analysis Plan   
A detailed statistical analysis plan will be drafted, reviewed and approved by the Steering 
Committee prior of the un-blinding of the data. 
11. FEASIBILITY 
Overall, about 140 study centers in Europe and USA, will participate in the study. Each 
study center is expected to recruit not less than 10 patients in the 18-month recruitment 
period. The overall study duration (first patient in/last patient out) is estimated to be 25 
months. 
12. INSURANCE 
All subjects participating in the study will have insurance coverage by the Promoter, 
which is in line with applicable laws and/or regulations. 
13. PROMOTER 
The Promoter of the study is FADOI Foundation. 

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14. REFERENCES 
1.    Prandoni P, Lensing AW, Piccioli A, et al. Recurrent venous thromboembolism 
and bleeding complications during anticoagulant treatment in patients with cancer 
and venous thrombosis. Blood 2002; 100: 3484-8. 
 
2.   Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, 
Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-
Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention 
of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) 
Investigators. Low-molecular-weight heparin versus a coumarin for the 
prevention of recurrent venous thromboembolism in patients with cancer. N Engl 
J Med. 2003; 349: 146-53.  
 
 
3.    Akl EA, Vasireddi SR, Gunukula S, Barba M, Sperati F, Terrenato I, Muti P, 
Schünemann H. Anticoagulation for the initial treatment of venous 
thromboembolism in patients with cancer. Cochrane Database Syst Rev. 
2011;(6):CD006649. Update in: Cochrane Database Syst Rev. 2014;6:CD006649.  
 
4.    Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman 
M, King CS, Morris TA, Sood N, Stevens SM, Vintch JR, Wells P, Woller SC, 
Moores L. Antithrombotic Therapy for VTE Disease: CHEST Guideline and 
Expert Panel Report. Chest. 2016; 149:315-52. 
 
 
5.    Lyman GH, Bohlke K, Khorana AA, Kuderer NM, Lee AY, Arcelus JY, 
Balaban EP, Clarke JM, Flowers CR, Francis CW, Gates LE, Kakkar AK, Key 
NS, Levine MN, Liebman HA, Tempero MA, Wong SL, Somerfield MR, Falanga 
A. Venous Thromboembolism Prophylaxis and Treatment in Patients With 
Cancer: American Society of Clinical Oncology Clinical Practice Guideline 
Update 2014 J Clin Oncol. 2015; 33:654-6 
 
 
6.  Lee AY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF,    
   Khorana AA; CATCH Investigators. Tinzaparin vs Warfarin for Treatment of  
   Acute Venous Thromboembolism in Patients With Active Cancer: A Randomized 
   Clinical Trial. JAMA. 2015; 314:677-86. 
 
 
7.   Van der Hulle T, den Exter PL, Kooiman J, van der Hoeven JJ, Huisman MV, 
Klok FA. Meta-analysis of the efficacy and safety of new oral anticoagulants in 

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patients with cancer-associated acute venous thromboembolism. J Thormb 
Haemost 2014; 12:1116-20. 
 
 
8. Prins MH, Lensing AW, Brighton TA, Lyons RM, Trajanovic M, Beyer- 
   Westendorf J, Pap AF, Berkowitz SD, Cohen AT, Kovacs MJ, Wells PS,  
   Prandoni P. et al. Oral rivaroxaban versus enoxaparin with vitamin K antagonist       
   for the treatment of symptomatic venous thromboembolism in patients with  
   cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of  
   two randomized controlled trials. Lancet Haematol 2014; 1: e37-46. 
 
9.  Goldhaber SZ, Kearon C, Kakkar AK, Schellong S, Eriksson H, Hantel S, 
Feuring M, Kreuzer J. Treatment with dabigatran or warfarin in patients with 
venous thromboembolism and cancer. Thromb Haemost 2015; 114:150-7.  
 
10. Agnelli G, Buller HR, Cohen A, Gallus AS, Lee TC, Pak R, Raskob GE, Weitz JI, 
Yamabe T. Oral apixaban for the treatment of venous thromboembolism in cancer 
patients: results from the AMPLIFY Trial. J Thromb Haemost 2015; 13:2187–91.  
  
11. Raskob GE, Buller HR, Angchaisuksiri P, et al. Edoxaban for long-term 
treatment of venous thromboembolism in cancer patients: a sub-analysis from 
the Hokusai-VTE trial ASH meeting abstract. Blood 2013; 122:211. 
 
 
12. Vedovati MC, Germini F, Agnelli G, Becattini C. Direct oral anticoagulants in 
patients with VTE and cancer: a systematic review and meta-analysis. Chest 
2015; 147:475-83. 
 
13. Deitcher SR, Kessler CM, Merli G, Rigas JR, Lyons RM, Fareed J; ONCENOX 
Investigators. Secondary prevention of venous thromboembolic events in 
patients with active cancer: enoxaparin alone versus initial enoxaparin followed 
by warfarin for a 180-day period. Clin Appl Thromb Hemost. 2006; 12:389-96 
 
 
14.  Posch F, Konisbrugge O, Zielinski C, Pabinger I, Ay C. Treatment of venous 
thromboembolism in patients with cancer a network meta-analysis comparing 
efficacy and safety of anticoagulants. Thromb Res 2015; 136:582-9 
 
 
15. Hokusai-VTE Investigators, Büller HR, Décousus H, Grosso MA, Mercuri M, 
Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, 

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Shi M, Verhamme P, Wells P. Edoxaban versus warfarin for the treatment of 
symptomatic venous thromboembolism. N Engl J Med. 2013; 369:1406-15. 
 
16. Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz 
U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral 
apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 
2013; 369:799-808 
 
 
17. EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous 
thromboembolism. N Engl J Med. 2010; 363:2499-510 
 
18. EINSTEIN Investigators. Oral Rivaroxaban for the Treatment of Symptomatic 
Pulmonary Embolism. N Engl J Med.  2012; 366: 1287-97 
 
 
19. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, 
Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran 
versus warfarin in the treatment of acute venous thromboembolism. N Engl J 
Med 2009; 361:2342-52. 
 
20. Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, 
Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II 
Trial Investigators. Treatment of acute venous thromboembolism with 
dabigatran or warfarin and pooled analysis. Circulation. 2014; 129:764-72 
 
.  
21. Campigotto F, Neuberg D, Zwicker JI. Accounting for death as a competing 
risk in cancer-associated thrombosis studies. Thromb Res. 2012;129 Suppl 
1:S85-7. 
 
22. Kohl M, Plischke M, Leffondré K, and Heinze G. PSHREG: A SAS macro for 
proportional and nonproportional subdistribution hazards regression. Comput 
Methods Programs Biomed. 2015; 118(2): 218–233. 
 
 
23.  Fine JP, Gray RJ. A Proportional Hazards Model for the Subdistribution of a 
Competing Risk. J Am Statist Ass 1999; 94: 496-509 
 
 

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15. APPENDICES 
 
Appendix 1 – Concomitant medications 
1. Prohibited Concomitant Medications 
Specifically excluded concomitant medications and cautions regarding other concomitant 
medications are provided below. The list in this appendix reflects exclusionary 
concomitant medications at the beginning of the study. If there are changes to this list 
during the study, the changes will be provided as an update to this appendix, but will not 
be considered a protocol amendment. 
1.1. Antiplatelet Drugs 
Dual antiplatelet therapy (any 2 antiplatelet agents including aspirin plus any other oral or 
IV antiplatelet drug) is prohibited while on study drug. If a clinical indication for dual 
antiplatelet therapy arises after randomization (eg, placement of an intracoronary stent), 
study drug should be interrupted and use of open-label LMWH/VKA is permitted at the 
physician’s discretion. 
Use of any antiplatelet medication, including aspirin, as single agent antiplatelet therapy 
is allowed while on study drug. 
It is strongly encouraged to restrict the dose of aspirin (if indicated) to ≤ 100 mg daily, 
although higher doses are permitted for a strong clinical indication (eg, development of 
an acute MI). 
Examples of non-aspirin oral antiplatelet agents include the following: 
- 
Thienopyridines: clopidogrel (Plavix®), ticlopidine (Ticlid®), prasugrel 
- 
(Effient™) 
- 
Dipyridamole: Persantine®, Aggrenox® 
- 
Pentoxifylline (Trental®) 

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- 
Sulfinpyrazone (Anturane®) 
- 
Ticagrelor (Brilinta®) 
- 
Cilostazol (Pletal®) 
IV antiplatelet agents include the following: 
- 
Glycoprotein IIb/IIIa inhibitors: Abciximab (ReoPro™), Eptifibatide 
- 
(Integrilin®), Tirofiban (Aggrastat®) 
- 
PGY12 Inhibitor: Cangrelor 
- 
Dextran 
1.2. Oral Anticoagulants Other Than Study Drug 
Oral anticoagulants including vitamin K antagonists (eg, warfarin), Factor IIa inhibitors 
(eg, dabigatran), and FXa inhibitors (eg, rivaroxaban, edoxaban) after randomization are 
prohibited (unless used to bridge a temporary study drug interruption). The only allowed 
oral antithrombotics are the study drugs. 
1.3. Parenteral Anticoagulants 
Parenteral anticoagulants such as heparin, LMWHs, direct thrombin inhibitors, and FXa 
inhibitors are prohibited except as specifically outlined in the protocol. For instance, 
LMWHs are allowed as lead-in therapy prior to edoxaban administration. Examples of 
prohibited parenteral anticoagulant medications, when used contrary to protocol 
specifications, include the following: 
- 
Low molecular weight heparins: dalteparin (Fragmin®), tinzaparin (Innohep®, 
- 
Logiparin®), reviparin (Clivarin®), nadroparin (Fraxiparine®), ardeparin 
(Normiflo®), certoparin (Sandoparin®), parnaparin (Fluxum®) 
- 
Direct thrombin inhibitors: bivalirudin (Angiomax®), argatroban (Acova®), 
desirudin (Ipravask®), lepirudin (Refludan®) 

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- 
FXa inhibitors: fondaparinux (Arixtra®) 
1.4. Intravenous Fibrinolytics 
Examples of fibrinolytics include the following: 
- 
Tissue plasminogen activator (alteplase, Activase®) 
- 
TNK (tenecteplase, TNKase®) 
- 
rPA (reteplase, Retavase®) 
- 
Streptokinase (Streptase®) 
- 
Anistreplase (Eminase®) 
If a subject requires treatment with a fibrinolytic agent, then study drug must be 
interrupted while the subject is taking the fibrinolytic drug and at least 24 hours after 
administration of a fibrinolytic agent. 
1.5. NSAIDs (Excluding Aspirin) 
While on study drug, NSAIDs cannot be taken for ≥ 4 days per week. Less frequent use 
of NSAIDs is permitted while on study drug. However, the Investigator should weigh the 
benefit/risk of NSAID use in combination with an oral anticoagulant for the individual 
subject. Examples of NSAIDs include the following: 
1.6. COX-2 Inhibitors 
While on study drug, COX-2 inhibitors cannot be taken for ≥ 4 days per week. Less 
frequent use of COX-2 inhibitors is permitted while on study drug. However, the 
Investigator should weigh the benefit/risk of COX-2 inhibitor use in combination with an 
oral anticoagulant for the individual subject.  
 
 
 

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1.7.  
Strong inhibitors of both CYP3A4 and P-gp: 
- 
atazanavir 
- 
boceprevir 
- 
clarithromycin 
- 
conivaptan 
- 
darunavir 
- 
darunavir/ritonavir 
- 
erythromycin 
- 
indinavir 
- 
indinavir/ritonavir 
- 
itraconazole 
- 
ketoconazole 
- 
lopinavir/ritonavir 
- 
nelfinavir 
- 
nefazodone 
- 
posaconazole 
- 
ritonavir 
- 
saquinavir 
- 
telaprevir 
- 
telithromycin 
- 
voriconazole  
 
1.8. Strong inducers of both CYP3A4 and P-gp: 
- 
avasimibe 
- 
carbamazepine 
- 
fosphenytoin 
- 
phenytoin 
- 
phenobarbital 
- 
primidone 
- 
rifampicin 
- 
St John’s wort 

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Appendix 2 – Quality of Life assessment / Anti-Clot Treatment Scale (ACTS) 
 
During the past 4 weeks… 
1. How much does the possibility of bleeding as a result of anti-clot treatment limit 
you from taking part in vigorous physical activities? (e.g. exercise, sports, 
dancing, etc.). 
  
2. How much does the possibility of bleeding as a result of anti-clot treatment limit 
you from taking part in your usual activities? (e.g. work, shopping, housework, 
etc.). 
  
3. How bothered are you by the possibility of bruising as a result of anti-clot 
treatment? 
  
4. How bothered are you by having to avoid other medicines (e.g. aspirin) as a result 
of anti-clot treatment? 
  
5. How much does anti-clot treatment limit your diet? (e.g. food or drink, including 
alcohol). 
  
6. How much of a hassle (inconvenience) are the daily aspects of anti-clot treatment? 
(e.g. remembering to take your medicine at a certain time, taking the correct dose 
of your medicine, following a diet, limiting alcohol, etc.).ù 
 
7. How much of a hassle (inconvenience) are the occasional aspects of anti-clot 
treatment? (e.g. the need for blood tests, going to or contacting the clinic/doctor, 
making arrangements for treatment while travelling, etc.). 
  
Now I want to ask you about daily and occasional aspects of your anticoagulation therapy 
during the past 4 weeks 

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8. How difficult is it to follow your anti-clot treatment? 
 
9. How time-consuming is your anti-clot treatment? 
 
10. How much do you worry about your anti-clot treatment? 
 
11. How frustrating is your anti-clot treatment? 
 
12. How much of a burden is your anti-clot treatment? 
 
13. Overall, how much of a negative impact has your anti-clot treatment had on your 
life? 
 
14. How confident are you that your anti-clot treatment will protect your health? (e.g. 
prevent blood clots, stroke, heart attack, DVT, embolism) 
 
15. How reassured do you feel because of your anti-clot treatment? 
 
16. How satisfied are you with your anti-clot treatment? 
 
17. Overall, how much of a positive impact has your anti-clot treatment had on your 
life? 
Copyright© 
Copyright of the ACTS instrument is held by Bayer AG, Germany (2006). All rights 
reserved. For information on or permission to use, please contact Mapi Research Trust; 
http://www.mapi-trust.org. 

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Appendix 3 – Schedule of assessments 
 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Unscheduled 
Visit (j) 
 
Screening 
Enrolment 
4-Wks 
3-mos 
End of Study 
Treatment 
End of Study 
UNSCH 
 
-72 hrs or 
less 
Day 1 
4-week after 
enrolment 
(± 7 days) 
3-month after 
enrolment 
(± 7 days) 
6-month after 
enrolment or 
Early 
withdrawal 
(± 7 days)
7 months after 
Randomization 
(± 7 days) 
Any time 
during the 
Study 
Treatment 
period 
Informed consent
x
Demography
x
Medical History
x
VTE Diagnosis (a)
x
Cancer History (b)
x
Cancer treatments (c)
x
Physical Examination and 
Vital Signs (d) 
x 
 
x 
x 
 
 
x 
Pregnancy test (for women 
of childbearing age)
x 
 
 
 
 
 
 
Serum chemistry (e)
x (f)
x
x
x
x
Hematology
x (g)
x (h)
x (h)
x (h)
x
Inclusion/Exclusion criteria
x
Eligibility criteria
x
Randomization
x
Drug dispensation
x
x(k)
x
Drug return and 
accountability
 
 
x 
x 
x 
 
 
Assess study outcomes (i.e. 
suspected recurrent VTE, 
bleeding) (i)
 
 
x 
x 
x 
x 
x 
Anti-Clot Treatment Scale 
(ACTS)
 
 
 
 
x 
 
 
Prior and Concomitant 
Medications
From 30 days prior to screening visit 
 
x 
AE / SAE 
 
From first study drug administration to 30 days after the last dose of study drug 
administration
x 
 
 
 
 
(a) Symptoms of VTE, site and confirmatory tests 
(b) Type, site and staging of cancer; date of diagnosis 
(c) Data on type and timing of cancer treatment (chemotherapy, radiotherapy, surgery) 
(d) Blood pressure, heart rate will be collected during at Screening and, if deemed necessary by the 
Investigator, during the unscheduled visit(s). Body weight will be collected at Screening and, for patients 
randomized to dalteparin, at Visit 3 and 4 (and Unscheduled, if any occurs), to correctly evaluate the drug 
dosage 
(e) Total Bilirubin (Direct and Indirect), ALT, AST, ALP, Serum creatinine, Creatinine clearance (Cockcroft 
Gault equation) 
(f) Samples obtained as part of routine care outside study auspices may be analyzed by local laboratories and 
the results used to qualify the subject provided the tests were performed within 72 hours of randomization 

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(g) At screening: Hematocrit, WBC, Hb, Plts, INR, PTT. Samples obtained as part of routine care outside study 
auspices may be analyzed by local laboratories and the results used to qualify the subject provided the tests 
were performed within 72 hours of randomization 
(h) At 4-wks, 3-mo, 6-mo: Hematocrit, WBC, Hb, Plts 
(i) For subjects who have discontinued study treatment, telephone query of health status (alive, occurrence of 
efficacy and safety endpoints and AEs/SAEs) is allowed. Subjects who have new symptoms should 
undergo further assessment as clinically appropriate, preferably at the study site whenever feasible 
(j) Unscheduled Visit(s): may occur at any time, during the study treatment period. Based on the specific 
reason why performing an unscheduled visit, the Investigator may decide if perform or not all the 
assessments marked in the table above 
(k) Applicable for Dalteparin patients only (Apixaban will not be dispensed at V3) 
 
 
 

Caravaggio Study Protocol 
FINAL Version 3.0, May 22nd 2018  
 
Proprietary & Confidential 
 
61
 
Appendix 4 – Protocol Signature Page (protocol writers) 
Protocol Title: 
 
APIXABAN FOR THE TREATMENT OF VENOUS THROMBOEMBOLISM IN 
PATIENTS WITH CANCER: A PROSPECTIVE RANDOMIZED OPEN BLINDED 
END-POINT (PROBE) STUDY (CARAVAGGIO) 
 
The present research protocol was subject to critical review and has been approved in the 
present version by the persons who undersigned. The information contained is consistent 
with the moral, ethical and scientific principles governing clinical as set out in the 
Declaration of Helsinki and the principles of ICH/GCP. 
 
Signatures: 
 
 
 ______________________________  
Date: May 22nd, 2018 
Giancarlo Agnelli MD, Study Chairman 
University of Perugia, Italy  
 
 
 
______________________________  
Date: May 22nd, 2018 
Giorgio Vescovo MD, FADOI 
 
 
_____________________________  
Date: May 22nd, 2018 
Mauro Campanini MD, FADOI 
 
 
______________________________  
Date: May 22nd, 2018 
Andrea Fontanella MD, FADOI 
 

Caravaggio Study Protocol 
FINAL Version 3.0, May 22nd 2018  
 
Proprietary & Confidential 
 
62
 
 
Appendix 5 – Protocol Signature Page (principal investigator) 
 
Protocol Title: 
 
APIXABAN FOR THE TREATMENT OF VENOUS THROMBOEMBOLISM IN 
PATIENTS WITH CANCER: A PROSPECTIVE RANDOMIZED OPEN BLINDED 
END-POINT (PROBE) STUDY (CARAVAGGIO) 
 
Declaration of Principal Investigator 
I have read the present research protocol and agree to conduct the study according to the 
protocol. 
I will enroll the first subject only after all ethical and regulatory requirements are fulfilled.  
I pledge to obtain written consent for study participation from all subjects. 
I pledge to retain all study-related documents and source data as described.  
 
 
 
Principal Investigator (Head of the study center): 
 
 
 
Name: __________________________________ 
 
 
Study Center: _____________________________ 
 
 
 
 
 
Signature: _______________________________Date: _______________________