Conditions: Venous Thromboembolism
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1170
Healthy volunteers: no

Brief summary:
Apixaban for the treatment of venous thromboembolism in patients with cancer: a prospective randomized open blinded end-point (PROBE) study

Detailed description:

Arms:
arm 1: orally administered, at the dose of 10 mg bid for 7 days, followed by 5 mg bid (total period of treatment: six months) arm 2: 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

Interventions: intervention 1: Apixaban intervention 2: Dalteparin
Intervention descriptions: intervention 1: Tablets intervention 2: Injections

Protocol document:
ICF_002.pdf: 
FADOI Foundation / Protocol Number FADOI 03.2016 
Page 1 of 19 
 
«PiFullName» 
Chesapeake IRB Approved Version 12 Feb 2018 
Revised «PIApprovalDate» 
 
 
 
Subject/Legally Authorized Representative Initials __________ 
 
 
INFORMED CONSENT FORM 
AND 
AUTHORIZATION TO DISCLOSE HEALTH INFORMATION 
 
Sponsor / Study Title: 
  
FADOI Foundation / “APIXABAN FOR THE TREATMENT OF 
VENOUS THROMBOEMBOLISM IN PATIENTS WITH 
CANCER: A PROSPECTIVE RANDOMIZED OPEN BLINDED-
ENDPOINT (PROBE) STUDY – THE CARAVAGGIO STUDY” 
 
Protocol Number: 
Final Version 2.0: 
 
IND #137387 
 
PROMOTER: 
 
FADOI 03.2016 
May 22, 2017 
 
 
 
FADOI Foundation 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Additional Contact(s): 
(Study Staff) 
 
«AdditionalStaffMemberContacts» 
 
Address: 
«PiLocations» 
 
This form is for use in a research study that may involve subjects who may or may not have the capacity 
to consent to take part in the study.  Accordingly, when the subject cannot legally consent to take part, 
pronouns “you” and “your” should be read as referring to the subject rather than the person (legally 
authorized representative) who is signing this form for the subject. In cases where the subject’s 
representative gives consent, the subject should be informed about the study to the extent possible given 
his/her understanding. During the course of the study, if the subject regains the capacity to consent, 
informed consent should be completed and the subject offered the ability to leave the study if desired. 
 
Introduction  
You are being asked to participate in a clinical research study under the care of your study doctor. Your 
participation is voluntary. This Informed Consent Form describes the purpose, procedures, benefits, risks, 
and costs of this clinical research study. It also describes the alternative procedures which are available to 
you and your right to withdraw from the study at any time.  
 
The study doctor or the research staff will explain the clinical research study and review this Informed 
Consent Form with you. They will explain any words or sentences that you do not clearly understand.  
 
You do not have to necessarily decide now whether or not you will participate in the research. Before you 
decide, you can talk to anyone you feel comfortable with about the research (family, friends or your 
doctor).   


FADOI Foundation / Protocol Number FADOI 03.2016 
Page 2 of 19 
 
«PiFullName» 
Chesapeake IRB Approved Version 12 Feb 2018 
Revised «PIApprovalDate» 
 
 
 
Subject/Legally Authorized Representative Initials __________ 
 
 
 
If you do agree to participate in the clinical research study, you will be asked to sign and date this 
Informed Consent Form. You will be given a signed and dated copy of this consent form, if you agree to 
participate. 
 
It is up to you to decide whether to participate in the study. If you decide not to participate, this will not 
affect the quality of medical care you receive. Your participation in this research study is completely 
voluntary.  
 
This study will be conducted according to the international regulations on clinical trials, and it has been 
reviewed and received approval from the Institutional Review Board (an independent group of people 
who protect subjects’ safety).  
 
Please inform the study doctor of your medical history (including any medications you are currently 
taking); otherwise your participation in this study may not be safe.  
 
Purpose of This Research Study 
 
We are doing a study on the treatment of venous thromboembolism disease associated with cancer. 
Venous thromboembolism, or VTE, encompasses two serious conditions: deep vein thrombosis (DVT), a 
blood clot in a deep vein, usually in the lower leg, thigh, or pelvis, which partially or totally blocks the 
flow of blood; and pulmonary embolism (PE), a blood clot that blocks one or more vessels in the lungs.  
 
The main purpose of this study is to demonstrate the clinical efficacy of a study drug called “apixaban” 
that could help in the treatment of your illness. 
 
Background 
 
This research study is a Phase IIIb clinical trial.  Phase IIIb clinical trials examine the safety and 
effectiveness of a study drug or study treatment, often comparing it to another known treatment. 
 
Patients with cancer who developed venous thromboembolism (VTE) are generally treated with an 
anticoagulation drug. Anticoagulation drugs, which are also called blood thinners, help prevent the 
blood from clotting in your blood vessels. 
 
Venous Thromboembolism is a disease combined of two serious conditions:  
1. Deep Vein Thrombosis (in short DVT)- a blood clot that is present in a deep vein in your body, 
usually in the lower leg, the thigh, or in the pelvis and can block partially or totally the flow of 
blood in your body.  
2. Pulmonary Embolism (in short PE)- a blood clot that is blocking one or more blood vessels in the 
lungs. 
 
Both dalteparin and apixaban are anticoagulation drugs. Apixaban and dalteparin are both approved in 
Europe and in the United States to treat patients with VTE, but only dalteparin is approved to treat VTE in 
patients with cancer.   
 


FADOI Foundation / Protocol Number FADOI 03.2016 
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«PiFullName» 
Chesapeake IRB Approved Version 12 Feb 2018 
Revised «PIApprovalDate» 
 
 
 
Subject/Legally Authorized Representative Initials __________ 
 
 
Apixaban is an oral drug that can be taken twice a day as a pill and is approved by the U.S. Food and 
Drug Administration (FDA) to treat VTE in people without cancer. Dalteparin is the standard treatment 
approved by the FDA for managing VTE in patients with cancer, and it is a drug that is injected under the 
skin (sub-cutaneous injection). 
 
In this research study, we are looking to see whether apixaban works the same as dalteparin, which is the 
standard treatment for cancer patients with VTE. 
 
Apixaban was tested in several clinical trials for management of VTE and was proved to be an effective 
anticoagulant. There were a low number of subjects with cancer in these trials.  
 
In some of the trials, subjects who have cancer associated VTE did do as well with apixaban as with the 
standard treatment warfarin. This current study is designed for cancer subjects only. 
 
This study is defined as an Investigators Initiated Study (IIS), where the sponsor (promoter) is a not-
for-profit Organization, called FADOI Foundation, an Italian Scientific Society of Internal 
Medicine. FADOI Foundation is responsible for the conduct and supervision of this study.  Bristol 
Meyer Squibb a pharmaceutical company is supporting the study by providing funding for the 
investigator initiated study and the apixaban, while Pfizer also a pharmaceutical company, will be 
providing the dalteparin. 
 
Baim Institute for Clinical Research (formerly known as HCRI, Harvard Clinical Research Institute), an 
academic Research Organization (ARO), will be managing the research sites in the United States. Baim 
Institute will be working with Exom Group, the contract research organization (CRO) for the European 
sites. 
 
Approximate Number of Subjects and the Expected Duration of Your Participation 
 
About 1200 subjects are expected to participate in this study worldwide, with approximately 200 subjects 
being enrolled across 20 centers in the United States. If you are enrolled into the study, the length of your 
participation is expected to be approximately seven months.  You will need to visit your enrolling site 3 
times over the course of the study. 
 
Study Treatments 
 
Subjects with cancer who have a DVT or PE are generally treated with a blood thinner, such as dalteparin. 
The aim of this study is to compare apixaban, which is taken by mouth, with dalteparin (a low molecular 
weight heparin drug [LMWH]), which is given as a shot, for the treatment of DVT and PE in subjects. 
 
Apixaban was developed by Bristol-Myers Squibb (BMS) and Pfizer and has been already approved for 
use in Europe and in the United States. It is currently used for the treatment of patients with DVT and PE, 
but has not been fully assessed for the treatment of DVT and PE in patients with cancer. 
 
Dalteparin is approved by FDA for the treatment of DVT and PE in patients with and without cancer.  
 


FADOI Foundation / Protocol Number FADOI 03.2016 
Page 4 of 19 
 
«PiFullName» 
Chesapeake IRB Approved Version 12 Feb 2018 
Revised «PIApprovalDate» 
 
 
 
Subject/Legally Authorized Representative Initials __________ 
 
 
If you agree to participate, you will be assigned to either the dalteparin or apixaban treatment group by a 
computer decision making system that randomly selects which study drug you will be treated with, by 
chance like the flip of a coin. There is a 50% chance that you will receive apixaban and a 50% chance that 
you will receive dalteparin. 
 
Study Procedures  
 
If you agree to participate in this study, you will be asked to: 
1. Sign and date the informed consent form; 
2. Provide your demographic information such as age, gender and ethnicity; 
3. Store the study drug in a safe place 
4. Avoid activities that could cause bleeding injuries 
5. Not enroll in any other clinical studies with experimental treatments that are known to affect 
coagulation (ability of blood to clot). 
6. Follow the study visit schedule and procedures, as outlined below: 
 
 
 


FADOI Foundation / Protocol Number FADOI 03.2016 
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«PiFullName» 
Chesapeake IRB Approved Version 12 Feb 2018 
Revised «PIApprovalDate» 
 
 
 
Subject/Legally Authorized Representative Initials __________ 
 
 
Research Study Plan: 
 
Visit 1  
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
 
Screening 
Enrollment/ 
Day 1 
Week 4 
Month 3 
End of Study 
Treatment End of Study 
 
-72 hours or 
less 
Day 1 
4 weeks  
after 
enrollment 
(± 7 days) 
3 months  
after 
enrollment 
(± 7 days) 
6 months 
after 
enrollment 
or early 
withdrawal 
(± 7 days) 
7 months 
after 
randomization 
(± 7 days) 
Informed Consent 
X 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
Medical History Review
X 
 
 
 
 
 
Cancer History and 
Treatments 
X 
 
 
 
 
 
Inclusion / Exclusion 
X 
 
 
 
 
 
Eligibility Criteria 
 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
 
Drug Dispensation 
 
X 
X 
X 
 
 
Physical Exam & Vital 
Signs 
X 
 
X 
X 
 
 
VTE Symptoms and 
Diagnosis 
X 
 
 
 
 
 
Blood Test 
X 
 
X 
X 
X 
 
Pregnancy Test 
X 
 
 
 
 
 
Serum Chemistry 
X 
 
X 
X 
X 
 
Hematology 
X 
 
X 
X 
X 
 
Assessment of VTE 
 
 
X 
X 
X 
X 
Assessment of Side 
Effects (AEs/SAEs) 
 From 1st study drug administration to 30 days after last dose of drug administration 
Review of prior / 
current medications 
From 30 days prior to screening visit 
Anti-Clot Treatment 
Scale Questionnaire 
 
 
 
 
X 
 
Study Drug Receipt/ 
Return 
 
X 
X 
X 
X 
 
 
Before you are enrolled in the study, you will undergo to a screening procedure in order to confirm that 
you meet the inclusion and exclusion criteria for this study. 
  
The following data will be collected at the screening visit:  
• Medical history, including your VTE symptoms and cancer diagnosis/treatment; 
• General physical exam and vital signs (like body weight, blood pressure, heart rate) 
• Pregnancy test for women of childbearing age 
• Blood and urine samples for clinical laboratory tests; 


FADOI Foundation / Protocol Number FADOI 03.2016 
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«PiFullName» 
Chesapeake IRB Approved Version 12 Feb 2018 
Revised «PIApprovalDate» 
 
 
 
Subject/Legally Authorized Representative Initials __________ 
 
 
• Medication you are currently taking or have taken in the last 30 days 
 
Study Treatment Period 
 
If you meet all of the inclusion and exclusion criteria for the study, you will be assigned to one of two 
study treatment groups.  The study doctor or research staff will give you instructions on taking the study 
drug you are assigned.  
 
While you are participating to the study you will undergo to regular medical examinations at certain 
times. These are at 4 weeks, 12 weeks, and 24 weeks after the start of the study treatment. At these visits, 
you should bring your remaining study drug and any empty study drug packages. 
 
After the week 24 visit, you will enter the follow-up period (lasting one month) and no additional study 
drug will be dispensed to you. Information about the follow-up visit period is in the next section. Your 
study doctor will determine if you should continue with blood thinners at the week 24 visit. 
 
During the visits at Week 4, Week 12, and Week 24, the following information will occur: 
 
• You will be asked about your symptoms, your medical status changes or hospitalizations since    
the last visit and any medicine that you are taking. 
• Blood samples will be taken for laboratory analysis. The amount of blood collected will be 
standard of care at your study doctor’s institution. Serum chemistry and hematology and platelet 
count results will be collected from the blood taken. 
• The research staff will review your adherence to the study drug by reviewing the amount you 
bring back to the visit. 
• At the 4 week and 12 week visits only: resupply of your assigned study drug (if needed) 
• At the 4 week and 12 week visits only: If you are assigned to the dalteparin group, your body 
weight will be measured to calculate the right dosage of study drug 
• At the 24 week visit only: You will be asked a series of questions about your anti-coagulation 
treatment which will take at most 15 minutes 
 
Follow-Up Period 
 
When you complete study treatments (following the week 24 visit) or if you withdraw early from the 
study treatment, you will enter the follow-up period. The follow up period lasts approximately one month 
from the date of study treatment completion or early withdraw.  
 
During this period your study doctor will continue to assess your health status. You will be asked to report 
important information on changes to your health; such as if you have recovered from your DVT, 
developed an illness or were hospitalized since your last visit. 
 
In the event it is necessary to further evaluate the safety or effectiveness of the study drug, it may be 
necessary to have access to additional information about your health status.  
 


FADOI Foundation / Protocol Number FADOI 03.2016 
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«PiFullName» 
Chesapeake IRB Approved Version 12 Feb 2018 
Revised «PIApprovalDate» 
 
 
 
Subject/Legally Authorized Representative Initials __________ 
 
 
Your study doctor may attempt to obtain study-related information about your health from you or from 
other sources, including your primary care physician and public sources such as national patient registries 
(for example, cancer registries). This may include contacting you again by phone or letter. 
 
Your Responsibilities 
 
At each visit: 
• You will be asked how you feel and about any side effects that you may have 
• You must inform your study doctor of any medication that you take while you are in this study. 
• You will have to bring back empty study drug packages and all unused study drug.  
• You will be asked to inform your study doctor or study staff of any changes to your address, 
telephone number, or other contact information. 
 
Possible Benefits to You for Taking Part in the Study 
 
There are no guaranteed benefits from participation in this study.  
 
Patients with cancer who have a DVT or a PE are generally treated with an anticoagulant or a blood 
thinner, like dalteparin or another low molecular weight heparin (LMWH) which have been proven to 
work in patients with cancer. These drugs are administered subcutaneously (via injection into the skin). 
Apixaban may be as good as dalteparin at treating blood clots in patients with cancer but may be easier to 
take because it is an oral medication. 
 
It is possible that by participating in this study your condition may improve or that this study may be 
helpful in developing a new therapy for others with similar illnesses.    
 
Even if you do not benefit directly from this research, knowledge gained from the study will contribute 
valuable information to researchers and doctors in the treatment of VTE in patients with cancer. 
 
Risks/Possible Adverse Drug Reactions 
 
Apixaban 
 
Apixaban belongs to the drug class of blood thinners (anticoagulants). Using any blood thinner is 
associated with a higher risk of bleeding. There is the possibility of clinically relevant bleeding in vital 
organs and increased bleeding during surgical operations or procedures. Clinically relevant bleeding can 
lead to death and/or disability. Apixaban may also cause minor bleeding, such as nose bleeds, gums or 
bruising bleeding. In a small group of subjects it has been reported as a low amount of blood in the urine, 
or stool or as small spots under the skin.  
 
Other possible side effects observed in subjects in previous studies of apixaban include:  
• Nausea 
• Constipation 
• Fever 
• Vomiting 
• Bloating 


FADOI Foundation / Protocol Number FADOI 03.2016 
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«PiFullName» 
Chesapeake IRB Approved Version 12 Feb 2018 
Revised «PIApprovalDate» 
 
 
 
Subject/Legally Authorized Representative Initials __________ 
 
 
• Joint pain 
• Sleep disturbances 
• Dizziness 
• Rashes 
• Itching 
• Headaches 
• Fatigue (feeling tired) 
• Stomach pains  
 
In subjects taking apixaban in clinical studies, uncommon but serious disorders were observed, such as:  
• Heart attack  
• Stroke  
• Death  
• Abnormalities in liver function 
 
Rarely: 
• Neuromuscular disorders have been observed 
 
These events occurred while subjects were taking apixaban alone or in combination with other drugs. This 
does not mean that apixaban was the cause of these events, but it may have helped provoke them. Adverse 
events (side effects) will be monitored closely in the study. If there is new information about the safety of 
the study drug, all researchers participating in this study will be notified and all subjects will be informed. 
Your study doctor will speak with you about any new safety information. 
 
Dalteparin 
 
The most common side effect associated with intake of dalteparin is bleeding. In some subjects treated 
with low molecular weight heparin (such as dalteparin) changes in liver function tests were observed. 
These changes were minor and in most cases, have disappeared if the subjects did not have other liver 
disease, such as infectious hepatitis.  
 
Other side effects include:  
• A decrease in blood platelets  
• Clinically relevant bleeding leading to death and/or disability  
• Fever 
• Nausea 
• Anemia 
• Swelling 
• Allergic Reactions 
 
Dalteparin can cause pain, irritation, redness and death of skin cells at the injection site.  
 


FADOI Foundation / Protocol Number FADOI 03.2016 
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«PiFullName» 
Chesapeake IRB Approved Version 12 Feb 2018 
Revised «PIApprovalDate» 
 
 
 
Subject/Legally Authorized Representative Initials __________ 
 
 
Additional Risks 
 
Blood samples taken for the study may cause fainting, vein inflammation, pain, bruising, bleeding or 
infection in the puncture area. The blood tests that are being done may also be needed by your cancer 
doctor and we will share the results. 
 
There are also possible risks of drug interactions between the study drug (apixaban) and the following 
drugs:  
• Strong antifungals drugs such as itraconazole and ketoconazole 
• Antibiotics such as clarithromycin 
• Telithromycin and rifampicin 
• Antiviral drugs such as ritonavir, indinavir, nelfinavir, saquinavir and atazanavir 
• Nefazodone 
 
There are also possible risks of drug interactions between the study drug and the following types of drugs, 
which could increase the risk of bleeding:  
• Salicylates (products containing aspirin) 
• NSAIDs (nonsteroidal anti-inflammatory drugs such as ibuprofen) 
• Anticoagulants 
• Anti-platelet drugs (such as clopidogrel or Plavix) 
 
You must also inform the study doctor about all the medicines you take or intend to take during the study. 
The study doctor may ask you to stop taking or change the dose of certain drugs or to replace them with 
other drugs. During this time, your symptoms may get worse.  If your symptoms get worse, tell the study 
doctor immediately. 
 
Risks Not Expected 
 
In addition to the risks listed above, the study drug and the study procedures may result in unwanted side 
effects that are unknown, unexpected or unforeseen. All medicines have a potential risk of allergic 
reaction that, if not treated promptly, could be fatal. There is always the possibility that you may 
experience a currently unknown or unexpected reaction. For this reason, it is important that you inform 
your study doctor about any sign, symptom or reaction you may have during the study. The study staff 
will monitor your health to rule out side effects; if necessary, the study doctor may decide to discontinue 
your participation in the study.  
 
Risks to Reproduction, Unborn Babies and Nursing Infants  
 
General Statement 
 
You must not be pregnant or breastfeeding, and you should not become pregnant or breastfeed while you 
are taking the study treatments.  
 
You must use an adequate method to avoid pregnancy for the duration of this study and for one month 
after the last dose of study drug. Acceptable birth control methods include hormonal contraceptives (pill, 
injection, implant, patch, vaginal ring), intrauterine device (IUD) or intrauterine system (IUS). 


FADOI Foundation / Protocol Number FADOI 03.2016 
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«PiFullName» 
Chesapeake IRB Approved Version 12 Feb 2018 
Revised «PIApprovalDate» 
 
 
 
Subject/Legally Authorized Representative Initials __________ 
 
 
 
You should immediately contact your study doctor if there is a change in your method to avoid pregnancy 
or if you start any prescription drug or other medication (including over-the-counter drugs and herbal 
supplements) not prescribed by the study doctor. 
 
Unforeseeable Risks 
 
There may be unknown risks to you, your unborn baby or nursing infant if you are or become pregnant 
during this study or are breastfeeding during this study. 
 
Laboratory & Animal Reproductive Toxicology Findings 
 
While laboratory and animal studies have been conducted to determine possible risks, the results do not 
necessarily show what will happen when the study drugs are used in humans.  
 
In pregnant rats and rabbits treated with apixaban there were no effects on the fetus. In a preliminary 
study of pregnant rats treated with apixaban, there was a slight increase in miscarriages. 
 
Occurrence of Pregnancy or Suspected Pregnancy 
 
If you become pregnant, suspect pregnancy or if you missed your period or it is late, or if you have a 
change in your usual menstrual cycle (for example, heavier bleeding during your period or bleeding 
between periods), you should immediately contact your study doctor. 
 
Discontinuation from the Study 
 
Should you become pregnant during this study, you will be immediately withdrawn from the trial or have 
the investigational product discontinued and be referred for obstetric care. 
 
The sponsor has not set aside any funds to pay for any aspects of obstetric, child or related care and does 
not plan to pay for them. 
 
Pregnancy Reporting 
 
In case of a pregnancy, your pregnancy and its outcome will be reported to the study sponsor. 
 
Information for Men with Partners of Childbearing Potential 
 
Even if the study drugs do not pose a risk to a woman who becomes pregnant while her male partner is a 
study subject, you are asked to inform your study doctor if your partner becomes pregnant while you are 
enrolled in this clinical trial, and you and your partner will be asked to provide information about the 
pregnancy outcome. 
 
The sponsor has not set aside any funds to pay for any aspects of obstetric, child or related care and does 
not plan to pay for them. 
 


FADOI Foundation / Protocol Number FADOI 03.2016 
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«PiFullName» 
Chesapeake IRB Approved Version 12 Feb 2018 
Revised «PIApprovalDate» 
 
 
 
Subject/Legally Authorized Representative Initials __________ 
 
 
Voluntary Participation/Discontinuation of Study Treatment of Withdrawal of Consent 
Your participation in this study is entirely voluntary. It is up to you to decide whether to take part or not. 
Even if you do decide to take part, you are free to discontinue study treatment or withdraw consent from 
the study at any time without giving a reason. This will not affect your future medical care in any way. 
Any information collected before you withdrew will be kept and used to complete the research.  
The Follow-up Period section describes activities that may begin if you decide to stop taking the study 
drug assigned to you. If you decide to stop the study treatments, your study doctor will ask you to come 
into the site for an End of Study Treatment Visit and then ask you participate in the follow-up activities as 
described in the Follow-up Period section.  
If you do not want to participate in any or all of the End of Study Treatment or follow-up activities, you 
must inform your study doctor in writing at the address listed on the first page of this form and clearly 
identify the activities you do not want. 
Please note that even if you withdraw consent for further follow-up or contacts, if the study doctor 
becomes aware of additional safety information, this will reported to the sponsor in order to comply with 
legal or regulatory requirements. 
Additional Reasons for Withdrawal from the Study  
 
The study doctor may decide to stop your participation in the study in the following cases: 
 
1. You do not follow the instructions given by the study doctor. 
2. It is found that you do not meet the requirements of the study. 
3. You develop a serious illness not related to participation in the study. 
4. The study doctor decides that you are not in your best interest to participate in the study or that the 
study drug is not benefitting you. 
5. Health authorities or the Institutional Review Board (IRB) decide to end the study. 
6. You become pregnant, you decide to have a child or you are breast-feeding during the study. 
 
If you decide to leave the study, you could undergo to certain tests and procedures. These tests and 
procedures include: 
• Hematological analysis (blood test) 
• Chemical analysis 
• Urinalysis 
• Vital signs (blood pressure and heart rate) 
• Evaluation of adverse events 
• Study outcomes 
• Evaluation of the use of the study drug 
• Collection of study drug 
• Urine pregnancy test (only for women of childbearing age) 
 
These tests are conducted to ensure you leave the study safely. The study doctor may also recommend 
other treatment. 


FADOI Foundation / Protocol Number FADOI 03.2016 
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«PiFullName» 
Chesapeake IRB Approved Version 12 Feb 2018 
Revised «PIApprovalDate» 
 
 
 
Subject/Legally Authorized Representative Initials __________ 
 
 
 
Costs for Taking Part In this Study 
 
Dalteparin and Apixaban will be given to you at no charge for the treatment period of this study. 
  
You will receive a stipend of $<< >> to compensate you for your travel to the study site for visits. You 
will be paid <<following the completed visit>> or <<at the end of your participation in the study, 
whichever you prefer>>.  If you discontinue early from the study, you will receive a pro-rated (partial) 
reimbursement amount based on how many study visits you completed. 
 
Your insurance (such as health insurance or Medicare) should be responsible for any expenses you have 
for your standard of care medical care. 
 
You should check your insurance policy to know what is exactly included.  If you do not have any or your 
insurance does not cover any or all of the costs related to your standard of care, they are your 
responsibility.  This includes co-pays or deductibles that are standard for your insurance.   The trial 
sponsor has an insurance policy in accordance to compensate for possible injuries related to study 
procedures. 
 
Compensation for Injury 
 
If as a result of your participation in this study, you are injured or hospitalized, you must immediately 
contact the study doctor. 
 
In the unlikely event you are injured as part of participating in this study, medical care is available. In the 
event of a research-related injury, you may contact the study doctor at the number of the first page of this 
form.  
 
If a research injury results from your participation in this study, medical treatment will be provided. The 
costs for medical care associated with the injury will be billed to you and/or your insurance.  A research-
related injury means injury caused by the product or procedure required by the research which you would 
not have experienced if you had not participated in the study 
 
There are no plans to provide payments or other forms of compensation (such as for lost wages, lost time, 
or discomfort).   
 
To pay these medical expenses, the sponsor will need to know some information about you like your 
name, date of birth, and social security number or Medicare Health Insurance Claim Number. This is 
because the sponsor has to check to see if you receive Medicare and if you do, report the payment it 
makes to Medicare. 
 
In no way does signing this consent form waive your legal rights nor does it relieve the investigators, 
Sponsor or involved institutions from their legal and professional responsibilities. 
 


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Subject/Legally Authorized Representative Initials __________ 
 
 
Alternative Treatment(s) 
 
You do not have to participate in this clinical study. Other approved commercially available drugs could 
be used for your procedure, including dalteparin as mentioned above.  Please speak with your study 
doctor about the risks and benefits of alternative treatments that are available to you. 
 
Voluntary Participation / Withdrawal 
 
Entering a research study is voluntary. If you do not want to be in a study or you stop the study at a later 
time, you will not be penalized or lose any benefits. 
 
New information relating to the study 
 
If any new information becomes available during the course of this study that may affect your willingness 
to participate, you will be informed.  
 
Confidentiality of Study Records and Medical Records 
 
We will take steps to keep your personal information private, but we cannot guarantee total 
confidentiality. All identifiable information about you will be replaced with a code before the information 
becomes research data and are sent to third-parties outside the study site for the research purpose. A list 
linking the code and your identity will be kept by the study site separate from the research data and will 
not be shared with sponsor or sponsor’s representative.  
 
All research data and records will be stored in a locked cabinet or on a secure electronic network.  
Electronic information will be stored with encryption and password protection to help prevent 
unauthorized access.  
 
Authorized persons of the sponsor or sponsor’s representatives and employees of the Regulatory 
authorities, such as the FDA, may have access to your medical records.   
 
Your name should not appear in any forms, reports, or publications, by the promoter FADOI, and its 
representatives, or by the study doctor and study team.  
 
We will not release information about you to others not listed above, unless required or permitted by law. 
Your research data and records will be kept for at least ten years after the study is completed, or for two 
years after the records are no longer needed by the Sponsor.  
 
For the purpose of this clinical study, your data (encrypted) will be transferred to the Italy (where the 
sponsor FADOI is based). The sponsor will ensure that your personal data is protected to the best of their 
abilities.  
 
The Baim Institute monitoring team will review data remotely and will have access to your identifiable 
information for the following reasons: 
• To confirm you are signing Informed Consent Form and Privacy consent 
• To ensure the study is being conducted correctly 


FADOI Foundation / Protocol Number FADOI 03.2016 
Page 14 of 19 
 
«PiFullName» 
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Revised «PIApprovalDate» 
 
 
 
Subject/Legally Authorized Representative Initials __________ 
 
 
 
Your identifiable information submitted to the Baim Institute monitoring team will be reviewed through a 
secure and access restricted system, such as a web-portal. Your information will not be saved or stored on 
desktops or personal drives. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include 
a summary of the results. You can search this Web site at any time. Information on this study will also be 
posted in a similar format on a European Web site at www.clinicaltrialsregister.eu. 
 
If you signed an electronic consent form (eICF), there are risks of storing or viewing the consent 
document on a personal electronic device (PED – IPad, Smart Phone, laptop, Tablet etc.), especially if 
that PED is shared with other people or is lost, hacked, or subject to a search warrant or subpoena. Unlike 
paper copies, electronic documents delivered directly to your PED may not be able to be permanently 
removed. 
 
If Your Study Doctor Cannot Locate You 
 
If your study doctor needs to follow up with you but cannot find you, he may try to learn your new 
address, telephone number or current health status by calling or writing to the person(s) named as your 
secondary contacts. If your study doctor cannot obtain information through your secondary contacts, he or 
she may ask for the assistance of a third-party representative and may share with that representative 
limited information about you, such as your name and last known address. The representative will consult 
public sources, such as public health registries and databases, to obtain your current contact information. 
The representative will only share this information with the study doctor, to help him complete the 
follow-up stage of the trial. Only the study doctor or a member of his team will contact you or your family 
members. 
 
Getting Answers to Your Questions or Concerns About the Study 
 
You can ask questions about this consent form or the study (before you decide to start the study, at any 
time during the study, or after completion of the study).  Questions may include: 
 
• Who to contact in the case of a research-related injury or illness; 
• Payment or compensation for being in the study, if any; 
• Your responsibilities as a study subject; 
• Eligibility to participate in the research; 
• The study doctor’s or study site’s decision to exclude you from participation; 
• Results of tests and/or procedures; 
• Other questions, concerns, or complaints. 
 
Contact the study doctor or study staff listed on the first page of this form with any questions, concerns 
or complaints.   
 
 
 


FADOI Foundation / Protocol Number FADOI 03.2016 
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Subject/Legally Authorized Representative Initials __________ 
 
 
Getting Answers to Your Questions About Your Rights as a Research Subject 
 
This study has been reviewed by an Institutional Review Board (IRB). This Committee reviewed this 
study to help ensure that your rights and welfare are protected and that this study is carried out in an 
ethical manner. 
 
For questions about your rights as a research subject, contact:  
 
• By mail: 
Study Subject Adviser 
Chesapeake IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
• or call toll free:        877-992-4724 
• or by email:              adviser@chesapeakeirb.com 
 
Please reference the following number when contacting the Study Subject Adviser: Pro00023966. 
 
If you seek emergency care, or if hospitalization is required, please inform the treating doctor that you are 
participating in a clinical trial. 
 
If any new information becomes available during the course of this study that may affect your willingness 
to participate, you will be informed. 
 
 
 


FADOI Foundation / Protocol Number FADOI 03.2016 
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VOLUNTEER'S STATEMENT 
 
__________________________________________________ 
________________ 
Study Subject (signature)  
  
 
 
 
Date 
 
__________________________________________________ 
Study Subject (printed) 
 
 
 
__________________________________________________ 
________________ 
Legally Authorized Representative (signature) 
 
 
Date 
(If Applicable) 
 
__________________________________________________ 
Legally Authorized Representative (printed)  
 
 
 
(If Applicable) 
 
__________________________________________________ 
________________ 
Signature of person who explained the study  
 
 
Date 
 
__________________________________________________ 
Printed name of person who explained the study  
 
Impartial Witness (if applicable)  
 
Applicable if the subject is unable to read or sign an independent witness to be present during the entire 
informed consent discussion. The witness must sign and personally date the informed consent form after 
the form and any other written information have been read and explained to the subject and he/she has 
given her/his verbal consent to participate in the study. 
 
 
__________________________________________________ 
________________ 
Witness (signature) 
 
 
 
 
 
 
Date 
First and Last Name 
 
__________________________________________________ 
Witness (printed) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


FADOI Foundation / Protocol Number FADOI 03.2016 
Page 17 of 19 
 
«PiFullName» 
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Subject/Legally Authorized Representative Initials __________ 
 
 
AUTHORIZATION TO USE AND DISCLOSE PROTECTED HEALTH INFORMATION 
 
The study doctor and their study support staff (collectively, the “study doctor”) may need to use and 
disclose your Protected Health Information (“PHI”) in order to conduct this study.  
 
PHI is medical information that identifies you, such as: 
• Name. 
• Address. 
• Social security number. 
• Medical record number. 
• And other details about you. 
Your PHI used in this study may include information: 
• Which is used to determine your eligibility, and 
• Collected from the procedures and tests that are carried out as a part of this study.  
This information may include, but is not limited to, the following types of medical information: 
• Past medical history including all medical records from your other health care providers.  
• Physical exam,  
• Routine laboratory tests,  
• Your response to any study treatments,  
• Information related to study visits and phone calls, and 
• Other tests or procedures which may be performed and are not listed. 
 
By signing this document, you give your permission for the study doctor to use your PHI for purposes of 
conducting this study for them to give this information to the sponsor and the sponsor’s key individuals. 
The “sponsor’s key individuals” may include: 
• Any parent or affiliate company of the sponsor. 
• Any person or company working for or with the sponsor to facilitate this study.  
 
Your original medical records from this study, which may contain your name and other direct identifiers, 
may be reviewed by the following; 
• Your study and medical records may be reviewed and/or copied by: 
o The sponsor and/or its representatives 
o Exom Group and/or its representatives 
o Baim Institute for Clinical Research and/or its representatives 
o Chesapeake IRB, the IRB overseeing this study. 
o Regulatory authorities, such as the FDA or similar regulators in other countries. 
 
The sponsor has agreed to use and disclose your PHI only as provided in this document.  The sponsor will 
use the study data, which may include your PHI, to establish the safety and efficacy of the study drug, to 
better understand the disease(s) or condition(s) being studied, to review the quality of this study, and to 
improve the design of future studies.  
 
 
 


FADOI Foundation / Protocol Number FADOI 03.2016 
Page 18 of 19 
 
«PiFullName» 
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Revised «PIApprovalDate» 
 
 
 
Subject/Legally Authorized Representative Initials __________ 
 
 
The sponsor and/or the study doctor may communicate information to doctors at other institutions 
participating in this study, people and companies with whom the sponsor works, the IRB overseeing this 
study, other ethics committees and regulatory agencies such as the FDA and similar regulatory agencies in 
other countries, for the same purposes mentioned in the previous sentence. Once PHI has been disclosed 
to a third party, federal privacy laws may no longer protect it from further disclosure. 
 
This authorization does not have an expiration date and permission to use and disclose your PHI will 
continue until such time as it is no longer required by the sponsor or the study doctor. In California and 
any other state that requires an expiration date, the Authorization will expire 50 years after you sign this 
authorization document. 
 
After the study is complete, you have the right to view and copy any PHI gathered about you for this 
study. This means your right to access inspect and/or amend the PHI gathered for this study will be 
suspended until this study is complete.  
 
You have a right to revoke your Authorization at any time. If you revoke it, your PHI will no longer be 
used for this study, except to the extent the parties to the research have already taken action based upon 
your Authorization or need the information to complete analysis and reports for this research. To revoke 
your Authorization, you must write to the study doctor at the address listed on the first page of this form, 
stating that you are revoking your Authorization to Use and Disclose Protected Health Information. If you 
revoke this Authorization, you will not be allowed to continue to be in this study.   
 
The study doctor will stop using and disclosing your PHI that has already been collected except to the 
extent necessary to ensure that the rest of this study is carried out appropriately. 
 
By signing this authorization document, you are giving your permission to use and share your PHI. If you 
do not give your permission, you will not be able to be in this study. 
 


FADOI Foundation / Protocol Number FADOI 03.2016 
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Subject/Legally Authorized Representative Initials __________ 
 
 
ACKNOWLEDGEMENT OF AUTHORIZATION 
 
 
__________________________________________________ 
First and Last Name of Subject (Print) 
 
 
__________________________________________________ 
________________ 
Signature of Subject  
 
 
 
 
 
Date 
 
 
__________________________________________________ 
 
Legally Authorized Representative Name (Print) 
 
 
 
(If Applicable) 
 
__________________________________________________ 
________________ 
Legally Authorized Representative (signature) 
 
 
Date 
(If Applicable) 
 
 
__________________________________________________ 
________________ 
Signature of person who explained the authorization 
 
Date 
 
 
__________________________________________________ 
 
Printed name of person who explained the authorization 
 
 
 
Impartial Witness (if applicable)  
 
Applicable if the subject is unable to read or sign an independent witness to be present during the entire 
informed consent and authorization discussion. The witness must sign and personally date the informed 
consent form after the form and any other written information have been read and explained to the 
subject and the subject has given verbal consent to participate in the study. 
 
__________________________________________________ 
________________ 
Witness (signature) 
 
 
 
 
 
 
Date 
First and Last Name 
 
__________________________________________________ 
 
Witness (printed) 
 

Prot_000.pdf: 
            
Proprietary & Confidential 
 
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 
Cardiology (ACC). 


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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) 
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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-
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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 
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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 
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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 
of Product Characteristics), the so called Suspected, Unexpected Serious Adverse 


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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) 
 
 
 


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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 
 


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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: _______________________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
Version: 1.3 
Date: 29OCT2019 
Sponsor: Fondazione FADOI 
Study Protocol: CARAVAGGIO (FADOI 03.2016) 
Filename: CARAVAGGIO SAP version 1.3 29OCT2019.docx 
Author: Claudio Iannacone 
Page 1 of 38 
 
 
Page 129 of 166 
 
 
 
 
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
Apixaban for the Treatment of Venous Thromboembolism 
in Patients with Cancer: A Prospective Randomized Open with 
Blinded End-Point (PROBE) Study - The Caravaggio Study 
(Study Code: FADOI 03.2016) 
 
Short Name: CARAVAGGIO 
 
IND/EUDRACT NUMBER 2016-003093-40 


 
Page 130 of 166 
Page 2 of 38 
 


STATISTICAL ANALYSIS PLAN 
Version: 1.3 
Date: 29OCT2019 
Sponsor: Fondazione FADOI 
Study Protocol: CARAVAGGIO (FADOI 03.2016) 
Filename: CARAVAGGIO SAP version 1.3 29OCT2019.docx 
Author: Claudio Iannacone 
 
 
Page 131 of 166 
Page 3 of 38 
 
Table of Contents 
1 
Distribution list .................................................................................................................................. 5 
2 
Modification history .......................................................................................................................... 5 
3 
List of abbreviations and definition of terms ................................................................................. 6 
4 
Introduction ....................................................................................................................................... 7 
5 
Study objectives ................................................................................................................................. 7 
5.1 
Primary objective ................................................................................................................................. 7 
5.2 
Secondary objectives ............................................................................................................................ 7 
6 
Study design ....................................................................................................................................... 8 
6.1 
General description .............................................................................................................................. 8 
6.2 
Study population .................................................................................................................................. 9 
6.3 
Inclusion criteria .................................................................................................................................. 9 
6.4 
Exclusion criteria ............................................................................................................................... 10 
6.5 
Stratification ....................................................................................................................................... 11 
6.6 
Treatment ........................................................................................................................................... 11 
6.7 
Blinding and procedures for unblinding the study ............................................................................. 11 
7 
Schedule of assessments .................................................................................................................. 12 
8 
Study procedures ............................................................................................................................. 13 
8.1 
Administrative procedures ................................................................................................................. 13 
8.2 
Tracking list / patient consent forms / data entry ............................................................................... 13 
9 
Statistical methods .......................................................................................................................... 14 
9.1 
Statistical and analytical plan ............................................................................................................. 14 
9.2 
General methodology ......................................................................................................................... 14 
9.3 
Sample size ........................................................................................................................................ 14 
9.4 
Rationale for the event rates in the two treatment arms ..................................................................... 14 
9.5 
Rationale for non-inferiority margin (delta) choice ........................................................................... 15 
9.6 
Adjustments for covariates ................................................................................................................. 16 
9.7 
Handling of data, dropouts and missing values .................................................................................. 16 
9.8 
Analysis populations .......................................................................................................................... 16 
9.9 
Multicenter studies ............................................................................................................................. 17 
9.10 
Multiple comparisons/multiplicity ..................................................................................................... 17 
9.11 
Examination of subgroups.................................................................................................................. 17 
9.12 
Study endpoints .................................................................................................................................. 18 
9.12.1 
Primary endpoint ................................................................................................................................. 18 
9.12.2 
Secondary efficacy endpoints .............................................................................................................. 19 
9.12.3 
Primary safety endpoint ...................................................................................................................... 19 
9.12.4 
Secondary safety endpoints ................................................................................................................. 20 
9.13 
Replacement policy ............................................................................................................................ 20 
10 
Statistical Analysis .......................................................................................................................... 21 
10.1 
Disposition of patients ....................................................................................................................... 21 


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Page 4 of 38 
10.2 
Demographic and other baseline characteristics ................................................................................ 21 
10.3 
Cancer diagnosis and history .............................................................................................................. 22 
10.4 
Venous thromboembolism ................................................................................................................. 22 
10.5 
Medical history and comorbidities ..................................................................................................... 23 
10.6 
Previous and concomitant medications .............................................................................................. 23 
10.7 
Study drug .......................................................................................................................................... 24 
10.8 
Analysis of efficacy ............................................................................................................................ 24 
10.8.1 
Analysis of primary endpoint .............................................................................................................. 24 
10.8.2 
Analysis of secondary endpoints ......................................................................................................... 25 
10.9 
Safety analyses ................................................................................................................................... 28 
10.9.1 
Adverse events .................................................................................................................................... 28 
10.9.2 
Laboratory evaluation.......................................................................................................................... 32 
10.9.3 
Vital Signs ........................................................................................................................................... 33 
10.9.4 
Interim analyses ................................................................................................................................... 33 
10.9.5 
Protocol deviations .............................................................................................................................. 33 
10.9.6 
Data and Safety Monitoring Board (DSMB) ....................................................................................... 33 
11 
Programming Conventions for Outputs ....................................................................................... 34 
12 
Partial Date Conventions ................................................................................................................ 35 
13 
References ........................................................................................................................................ 37 
14 
Tables, line listings and figures shells ............................................................................................ 38 


 
 
Page 133 of 166 
STATISTICAL ANALYSIS PLAN 
Version: 1.3 
Date: 29OCT2019 
Sponsor: Fondazione FADOI 
Study Protocol: CARAVAGGIO (FADOI 03.2016) 
1 Distribution list 
 
 
 
Name 
Title 
Affiliation 
Claudio Iannacone 
Senior Biostatistician 
SPARC Consulting, Milan 
Federico Montuori 
Biostatistician 
SPARC Consulting, Milan 
Marco Villa 
Clinical Operations Director 
EXOM Group, Milan 
Giancarlo Agnelli 
Principal Investigator & Study 
Chairman 
University of Perugia, Perugia 
 
 
 
2 Modification history 
 
 
Unique 
Identifier 
for this 
Version 
Date of the 
Document 
Version 
Author 
Significant Changes from 
Previous Authorized Version 
1.0 
23MAY2017 
Federica Brunero 
n.a. 
1.1 
05SEP2017 
Federica Brunero 
Previous version not yet approved. 
Minor changes to the text were made. 
1.2 
02MAR2018 
Federica Brunero 
Previous version not yet approved. 
Minor changes to the text were made. 
1.3 
29OCT2019 
Claudio Iannacone 
Previous version not yet approved. 
Minor changes to the text were made. 
Added more details about the inferential 
statistical analysis to be performed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Filename: CARAVAGGIO SAP version 1.3 29OCT2019.docx 
Author: Claudio Iannacone 
Page 5 of 38 


STATISTICAL ANALYSIS PLAN 
Version: 1.3 
Date: 29OCT2019 
Sponsor: Fondazione FADOI 
Study Protocol: CARAVAGGIO (FADOI 03.2016) 
Filename: CARAVAGGIO SAP version 1.3 29OCT2019.docx 
Author: Claudio Iannacone 
 
 
 
Page 134 of 166 
Page 6 of 38 
 
3 List of abbreviations and definition of terms 
The following abbreviations and special terms are used in this document. 
 
Abbreviation 
Definition 
ACTS 
Anti-Clot Treatment Scale 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
BMI 
Body Mass Index 
CRF 
Case Report Form 
DVT 
Deep Vein Thrombosis 
FADOI 
Italian Federation of Hospital Internists 
FAS 
Full Analysis Set 
HR 
Hazard Ratio 
ITT 
Intention-To-Treat 
LMWH 
Low Molecular Weight Heparin 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intention-To-Treat 
NSCLC 
Non-Small Cell Lung Cancer 
PE 
Pulmonary Embolism 
PROBE 
Prospective Randomized Open-label, Blinded End-point 
PP 
Per-Protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System (software) 
SCLC 
Small Cell Lung Cancer 
SOC 
System Organ Class 
TEAE 
Treatment Emergent Adverse Event 
TESAE 
Treatment Emergent Serious Adverse Event 
VTE 
Venous ThromboEmbolism 
WHO 
World Health Organization 
WHO-DD 
World Health Organization – Drug Dictionary 


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4 Introduction 
This document reports on the rules, conventions and table shells to be used in the analysis of data of 
the clinical study FADOI 03.2016 (short title: CARAVAGGIO) of Fondazione FADOI. 
It describes, in details, the data and variables to be summarized and analyzed, including specifics of 
the statistical analyses to be performed. 
5 Study objectives 
5.1 
Primary objective 
To assess whether oral apixaban is non-inferior to the subcutaneous low molecular weight heparin 
(LMWH) dalteparin for the treatment of acute proximal deep vein thrombosis (DVT) and/or 
pulmonary embolism (PE) in patients with cancer, with respect to the primary outcome of the study 
which is objectively confirmed recurrent DVT or PE occurring during the intended study treatment 
period (6 months), which includes proximal DVT of the lower limbs (symptomatic or incidental), 
symptomatic DVT of the upper limbs and PE (symptomatic, incidental or fatal). 
5.2 
Secondary objectives 
Secondary objectives of this study are: 
Concerning safety 
1) To characterize apixaban therapy relative to subcutaneous dalteparin therapy in adjudicated 
major bleeding during the actual study treatment period plus 72 hours. 
2) To characterize apixaban therapy relative to subcutaneous dalteparin therapy in the composite 
of adjudicated major bleeding and adjudicated clinically relevant nonmajor bleeding during 
the actual study treatment period plus 72 hours. 
3) To characterize apixaban therapy relative to subcutaneous dalteparin therapy in adjudicated 
clinically relevant nonmajor bleeding during the actual study treatment period plus 72 hours. 
 
Concerning efficacy 
 
1) To assess whether oral apixaban is non-inferior to the subcutaneous dalteparin for the 
treatment of acute proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in 
patients with cancer, with respect to one of the following, taken individually: 
a. Recurrence of proximal DVT of the lower limbs (symptomatic or unsuspected) 
b. Recurrence of DVT of the upper limbs (symptomatic) 
c. Recurrence of pulmonary embolism (symptomatic or unsuspected) 
2) To assess whether oral apixaban is non-inferior to the subcutaneous dalteparin for the 
treatment of acute proximal DVT and/or pulmonary embolism (PE) in patients with cancer, 
with respect to symptomatic recurrence of Venous Thromboembolism (VTE). 
3) To assess whether oral apixaban is non-inferior to the subcutaneous dalteparin for the 
treatment of acute proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in 
patients with cancer, with respect to confirmed recurrence of proximal DVT or PE plus major 
bleeding. 


STATISTICAL ANALYSIS PLAN 
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Author: Claudio Iannacone 
 
 
 
Page 136 of 166 
Confirmed DVT 
without 
symptomatic 
< 72 
Apixaban 
10 mg bid 
Apixaban 
5 mg bid 
R
Dalteparin 200 IU/kg od        Dalteparin 150 IU/kg od 
30 day 
observation 
period 
Day 1 
Day 7 
Day 28 
6 months 
Confirmed PE 
with or without 
symptomatic DVT 
* Maximum time allowed between diagnosis and randomization 
Page 8 of 38 
 
4) To compare the overall survival between the two treatment groups (all causes of death). 
5) To compare the event free survival between the two treatment groups, where the event is a 
composite of the primary efficacy outcome plus major bleeding plus death due to all causes. 
6) To compare the event free survival between the two treatment groups, where the event is a 
composite of the primary efficacy outcome plus death due to all causes. 
7) To compare oral apixaban with the subcutaneous dalteparin for the treatment of acute 
proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in patients with 
cancer, with respect to any fatal or not fatal cardiovascular event (including acute myocardial 
infarction or ischemic stroke). 
8) To compare oral apixaban with the subcutaneous the subcutaneous dalteparin for the treatment 
of acute proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in patients 
with cancer, with respect to all venous thromboembolic events (including splancnic vein 
thrombosis and cerebral vein thrombosis). 
9) To compare quality of life evaluation between the two treatment groups (ACTS Scale). 
6 Study design 
6.1 
General description 
This is a multinational, prospective, randomized, open-label, with blinded end-point (PROBE), non- 
inferiority study comparing apixaban to the LMWH dalteparin in the treatment of VTE in patients 
with cancer. 
The aim of this study is to assess whether apixaban is non-inferior to the LMWH dalteparin for the 
treatment of acute proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE) in patients 
with cancer. 
Patients with cancer and acute 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 
and the signature of the informed consent form. Patients will be randomized on a 1:1 basis to receive 
either: 
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 18,000 IU. 
Enrolled patients will receive the study drug for 6 months. 
 


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Page 137 of 166 
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Randomization will be centralized and stratified by: 
1) symptomatic vs. unsuspected VTE 
2) active cancer vs. history of cancer 
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 symptoms of major 
bleeding develop. A clinical examination and objective tests will be performed if the patient develops 
symptoms or signs suggestive of recurrent VTE or major bleeding. 
6.2 
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 and the signature of the 
informed consent form. This study planned to enroll a total of about 1,168 patients. 
In order to be enrolled, patients had to fulfill the inclusion and exclusion criteria listed in the 
paragraphs 6.3 (Inclusion criteria) and 6.4 (Exclusion criteria). 
6.3 
Inclusion criteria 
To be eligible for this trial, patients have to meet the following criteria: 
1. 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 defect(s) at compression 
ultrasonography, venography, CT venography or MR venography involving the popliteal vein or 
more proximal veins. 
The diagnosis of PE requires one or more among: 


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• 
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; 
• 
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 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 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. 
6.4 
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) 
Three 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 of the Study Protocol); 
 
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 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 higher than the upper limit of the normal range; 


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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) Patients 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 participates in the study. 
6.5 
Stratification 
Randomization will be centralized and stratified by: 
1) symptomatic vs. unsuspected VTE 
2) active cancer vs. history of cancer 
6.6 
Treatment 
Patients will be randomized in a 1:1 ratio 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. 
6.7 
Blinding and procedures for unblinding the study 
This is an open-label clinical study; therefore, no blinding procedures are applied. 


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7 Schedule of assessments 
The schedule of assessments is reported in the study flow-chart (Table 1). 
Table 1: Schedule of assessments 
 
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Unscheduled 
Visit (i) 
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 months after 
Randomization 
(± 7 days) 
Any time 
during the 
Study 
Treatment 
period 
(± 7 days) 
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 
x 
x 
x 
x 
Hematology 
x (f) 
x (g) 
x (g) 
x (g) 
x 
Inclusion/Exclusion 
criteria 
x 
Eligibility criteria 
x 
Randomization 
x 
Drug dispensation 
x 
x 
x 
Drug return and 
accountability 
x 
x 
x 
Assess study 
outcomes (i.e. 
suspected recurrent 
VTE, bleeding) (h) 
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) At screening: Hematocrit, WBC, Hb, Plts, INR, PTT 
(g) At 4-wks, 3-mo, 6-mo: Hematocrit, WBC, Hb, Plts 
(h) 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 
(i) 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 


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8 Study procedures 
8.1 
Administrative procedures 
The study will be coordinated by the Internal Emergency and Vascular 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. 
An independent committee, whose members will be unware of treatment allocation, will adjudicate 
all suspected outcome events and the qualifying diagnosis, the anatomical extent of the initial DVT 
or PE. 
Exom Group, Milan, Italy, through formal nomination, is the entity allowed to handle data processing 
and it is in charge of the study analysis. 
All analysis results will be exclusively produced in aggregate data and will not in any way referred 
to individual patients. 
8.2 
Tracking list / patient consent forms / data entry 
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 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 that the primary physician is to be 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- 
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9 Statistical methods 
Deviations from methods described in this document might appear. In case of such deviations, the 
reason for the deviation will be stated in the statistical report. 
9.1 
Statistical and analytical plan 
This statistical analysis plan is based on the study protocol version 3.0 dated 22 May 2018 and 
describes the statistical analyses to be conducted for the final assessment of the study data. 
9.2 
General methodology 
All data summaries and listings will be performed using the SAS System version 9.4 under Windows 
10 PRO operating system. The statistical analysis will be performed by SPARC Consulting, Milan, 
Italy on behalf of Exom Group, Milan, Italy. 
Continuous-scaled variables will be summarized with means, medians, standard deviations, quartiles, 
and minimum and maximum values. Categorical variables will be summarized using patient counts 
and percentages. 
Two-sided 95% confidence intervals for proportions and means will also be produced, where 
clinically appropriate. 
The statistical testing will be conducted at the α level of 0.05 (two-sided) unless differently specified 
(primary end-point analysis). Confidence intervals will be calculated at the confidence level of 95%. 
9.3 
Sample size 
The study has been designed to test the hypothesis that apixaban would be non-inferior to dalteparin 
with respect to the primary study 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 1,168 
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). 
9.4 
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) assessment 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 recurrent VTE in the CLOT trial and symptomatic 


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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 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) vs 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 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. 
9.5 
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 
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 


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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) 
• 
1.8 for AMPLIFY (Apixaban) 
• 
2.0 for EINSTEIN DVT and EINSTEIN PE (Rivaroxaban) 
• 
2.75 for RECOVER I and II (Dabigatran) 
All the above-mentioned studies were considered valid by EMA and FDA for registration of direct 
oral anticoagulants for the indication “treatment of VTE”. 
9.6 
Adjustments for covariates 
All Cox’s proportional hazard models and the linear effects models for quality of life evaluation will 
be performed using treatment group, center, symptomatic vs unsuspected VTE and active cancer vs 
history of cancer and interaction of stratification factors as dummy covariates. 
9.7 
Handling of data, dropouts and missing values 
For the Burden score of ACTS scale, no imputation on missing data will be applied if ≥ 7 items are 
incomplete; otherwise, the Burden score is calculated as the mean of the complete items score x 12. 
For the Benefit score of ACTS scale, no imputation on missing data will be applied if ≥ 2 items are 
incomplete; otherwise, the Burden score is calculated as the mean of the complete items score x 3. 
In the situation where the event date is partial or missing, the date will appear partial or missing in 
the listings, and any corresponding durations will be presented based on the imputations specified in 
Section 12 “Partial Date Conventions”. 
Other missing data will not be replaced. 
The number of patients with missing data will be presented under the “Unknown” category. 
Missing values will be included in the denominator count when computing percentages. 
When continuous data are being summarized, only the non-missing values will be evaluated for 
computing summary statistics. 
9.8 
Analysis populations 
The following analysis populations will be considered in the statistical analysis: 
• The enrolled subjects (ENR) set includes all subjects who signed the informed consent form. 
• The Intent-to-Treat (ITT) analysis set includes all randomized subjects. Subjects will be 
categorized to the group to which they were assigned at randomization, regardless of the 
treatment actually received. 
• The modified Intent-to-Treat set (mITT) includes all randomized subjects who received at 
least one dose of the study drugs (this is the primary efficacy data set). Subjects will be 


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categorized to the group to which they were assigned at randomization regardless of the 
treatment actually received. 
• The Safety (SAF) Analysis set includes all randomized subjects with at least one 
documented administration of any study drug. 
• The Per Protocol (PP) analysis set will consist of all patients in the ITT analysis set 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. Major protocol violations are the following: 
o Less than 80% or more than 120% compliance with intended study medications; 
o Use of prohibited concomitant medications (see Appendix 1 of the Study Protocol): 
dual antiplatelet therapy (any two antiplatelet agents including aspirin plus any other 
oral or IV antiplatelet drug), oral anticoagulants other than study drug, parenteral 
anticoagulants (if used contrary to protocol specifications), intravenous fibrinolytics, 
NSAIDs (if taken for ≥ 4 days per week); 
o Error in treatment dispensing resulting in a subject being dosed with an incorrect 
treatment. 
The decision whether a protocol deviation is major or not for the classification of patients to 
the Per-Protocol analysis set will be made case-by case in the blind data review meeting that 
will be held before the database lock. 
9.9 
Multicenter studies 
Study center is 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. 
9.10 Multiple comparisons/multiplicity 
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. 
9.11 Examination of subgroups 
The treatment effects on the primary variable will be characterized for all subgroups outlined in Table 
2. 
Analyses will be performed on the primary efficacy dataset (mITT) only. 
No hypothesis testing will be conducted among the categories of the subgroups. 
Statistics presented for each category of the subgroups will include the apixaban-to-comparator 
Hazard Ratio adjusted for the competing risk of death unrelated to VTE with the associated two- sided 
95% CI (by resorting to the Fine & Gray regression model using treatment group, center, symptomatic 
vs unsuspected VTE, and active cancer vs history of cancer as dummy covariates). 


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Table 2: Subgroups 
 
 
Grouping Variable 
Category 
Index event 
Proximal DVT 
PE 
Age 
< 65 years old 
 65 to < 75 years old 
 75 years old 
Gender 
Male 
Female 
BMI at baseline 
≤ 25 kg/m2 
>25-≤30 kg/m2 
>30 kg/m2 
Level of Renal Impairment (by means of creatinine 
clearance) at baseline 
Severe (≤ 30 ml/min) 
Mild or Moderate (>30-≤ 80 ml/min) 
Normal (>80 ml/min) 
Active Cancer at baseline 
Active Cancer 
Absence of active cancer 
Anticancer treatment during the study period 
Any CHT/RT 
No CHT/RT treatment 
Symptomatic VTE at Baseline 
Symptomatic 
Unsuspected 
 
9.12 Study endpoints 
9.12.1 Primary endpoint 
The primary efficacy endpoint is the time from randomization to the first recurrent thromboembolic 
event. 
A thromboembolic event is a confirmed recurrent proximal DVT or PE, 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 seen on the second imaging test but not evident on the original images, or on an interval 
imaging test 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. 


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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; 
• 
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. 
9.12.2 Secondary efficacy endpoints 
1. The individual components of the primary efficacy outcome: 
a. Time from randomization to the first recurrent ipsilateral proximal DVT of the lower 
limbs (symptomatic or unsuspected) 
b. Time from randomization to the first recurrent contralateral proximal DVT of the 
lower limbs (symptomatic or unsuspected) 
c. Time from randomization to the first recurrent DVT of the upper limbs 
(symptomatic) 
d. Time from randomization to the first recurrent pulmonary embolism (symptomatic or 
unsuspected) 
2. Time from randomization to the first symptomatic recurrent thromboembolic event. 
3. Time from randomization to the composite of primary efficacy outcome plus major bleeding 
(whichever occurs first). 
4. Time from randomization to death (all causes) (Overall Survival). 
5. Time from randomization to the composite of primary efficacy outcome plus major bleeding 
plus death (all causes) (whichever occurs first). 
6. Time from randomization to the occurrence of any fatal or not fatal cardiovascular event. 
7. Time from randomization to thromboembolic events at sites other than DVT and PE (i.e. 
ischemic stroke, myocardial infarction, other venous thromboembolic events or other arterial 
thromboembolic events) 
8. Total score and subscales of the Anti-Clot Treatment Scale (ACTS, a Quality of life 
evaluation). 
9.12.3 Primary safety endpoint 
The primary safety endpoint is the proportion of subjects with major bleeding, defined (as per ISTH 
guidelines), as acute clinically overt bleeding associated with one or more of the following: 


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• 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. 
9.12.4 Secondary safety endpoints 
• Proportion of subjects with a clinically relevant non-major bleeding event, defined as acute 
clinically overt bleeding that does not meet the criteria for major and consists of: 
o any bleeding compromising hemodynamics; 
o spontaneous hematoma larger than 25 cm2, or 100 cm2 if there was a  traumatic 
cause; 
o intramuscular hematoma documented by ultrasonography; 
o epistaxis or gingival bleeding requiring tamponade or other medical intervention or 
bleeding from venipuncture for >5 minutes; 
o hematuria that was macroscopic and was spontaneous or lasted for more than 24 hours 
after invasive procedures; 
o hemoptysis, hematemesis or spontaneous rectal bleeding requiring endoscopy or other 
medical intervention; 
o 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. 
• Proportion of subjects with clinically relevant bleeding defined as the composite of major and 
clinically relevant non-major bleeding. 
• Proportion of subjects who permanently and prematurely discontinued study drug due to 
safety reasons. 
9.13 Replacement policy 
No patient prematurely discontinued from the study for any reason will be replaced. 


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10 Statistical Analysis 
10.1 Disposition of patients 
Tables and data listings will be presented for ENR population. 
The number of subjects enrolled into the study, and the number of subjects enrolled but not 
randomized together with the reasons for not being randomized will be summarized. 
An individual data listing of the patients who did not satisfy the eligibility criteria will be presented 
(screening log). 
The frequency of patients enrolled in each site will be tabulated by randomized treatment group and 
for all randomized patients combined. 
A summary of analysis populations and an individual data listing of the reasons for patients’ exclusion 
from each population will be presented. 
The summaries of disposition described below will also be presented by randomization stratification 
factor - index event. 
The number of treated patients, the number of patients who completed 6 months of study treatment, 
and the number of subjects discontinuing study therapy together with the reasons for discontinuation 
will be summarized by treatment group. 
The reasons for discontinuation will be taken from the End-of-Treatment Status page of the CRF. 
Discontinuations from study drug due to AEs will further be summarized by the AE type: ipsilateral 
proximal DVT lower limbs, contralateral proximal DVT lower limbs, DVT upper limbs, PE, 
bleeding, acute myocardial infarction (MI), ischemic stroke, other venous thromboembolic events, 
other arterial thromboembolic events, and other adverse events. 
10.2 Demographic and other baseline characteristics 
Demographic and baseline patient characteristics will be summarized by treatment group all 
patients in the ITT set. 
The baseline values are those measured at the Screening Visit and are the following: 
• Age (years) – calculated as the difference between the year of informed consent and the year 
of birth. 
• Gender 
• Ethnicity (Hispanic or Latino / Not Hispanic or Latino) 
• Race (White / Black or African American / Asian / American Indian or Alaska native / Native 
Hawaiian or other pacific islander / Other / Not applicable (because forbidden by the national 
law)) 
• Height (cm) 
• Weight (kg) 
• BMI (kg/m2) 
• Systolic Blood Pressure and Diastolic Blood Pressure (mmHg) 
• Heart Rate (bpm) 
• ECOG Performance Status (1 / 2 / 3 / 4 / 5) 
• Pregnancy test (for females with childbearing potential): 


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o Done / Not done 
o Result (Negative / Positive) 
• Physical examination: 
o Done / Not done 
o Result (Normal / Abnormal Clinically Significant / Abnormal Not Clinically 
Significant) 
10.3 Cancer diagnosis and history 
The following variables on tumor diagnosis and history will be summarized by treatment group 
with default statistics for all patients in the ITT set: 
• Diagnosis of cancer other than basal-cell or squamous-cell carcinoma of the skin or primary 
tumor or acute leukemia? (Yes / No); 
• Intracerebral metastasis? (Yes / No); 
• Time of diagnosis (within 6 months before the study inclusion / between 6 months and 2 
years before the study inclusion); 
• Treatment for cancer (None in the 6 months prior to study inclusion / at study inclusion / 
during 6 months prior to randomization); 
• Recurrent or locally advanced metastatic cancer (Yes / No); 
• Time from diagnosis (months), calculated as: 
(Date of screening visit – date of diagnosis + 1) / 30.4. 
• Primary Tumor site (Biliary tract / Bladder / Bone-soft tissue / Brain / Breast / Colorectal / 
Esophagus / Head and neck / Hematological malignancy / Hepatocellular carcinoma / Kidney 
/ Lung / Ovary / Pancreas / Prostate Gland / Skin – Melanoma / Skin – Basal Cell Carcinoma 
/ Skin – Squamous Cell Carcinoma / Stomach / Testicular cancer / Thyroid / Uterus / Other) 
• If hematological malignancy: 
o Type of malignancy (Acute lymphocytic leukemia / Chronic lymphocytic leukemia / 
Acute myeloid leukemia / Chronic myeloid leukemia / Leukemia – other / Non- 
Hodgkins lymphoma / Hodgkins lymphoma / Multiple myeloma / Other); 
o Complete remission (Yes / No); 
• If lung, type of tumor (SCLC / NSCLC / Other) 
• Histological type (Adenocarcinoma / Squamous cell carcinoma / Sarcoma / Neuroendocrine 
/ Unknown / Not applicable / Other) 
• Staging at study entry (Localized / Regional / Distant / Unknown / Not applicable) 
10.4 Venous thromboembolism 
The following variables on venous thromboembolism characteristics will be summarized by treatment 
group with default statistics for all patients in the ITT set: 
• Type of VTE (DVT = Deep Vein Thrombosis / PE = Pulmonary Embolism) 
• Time from confirmed diagnosis (months), calculated as: (date of screening visit – date of 
confirmed diagnosis +1)/30.4. 


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• Symptomatic (Yes / No) 
• If type of VTE is DVT: 
o Specific type of DVT (Symptomatic DVT proximal lower limb / Unsuspected DVT 
proximal lower limb) 
o Location of DVT (Vena Cava, Vena iliaca right / Vena iliaca left / Vena iliaca bilateral, 
Right femoral vein / Left femoral vein / Bilateral femoral vein, Right popliteal vein / 
Left Popliteal vein, / Bilateral Popliteal vein, Right Distal vein / Left Distal vein / 
Bilateral Distal vein, Other) 
o If symptomatic, type of symptoms (Pain, Redness, Calf pain of tenderness, Swelling 
of extremities, Tenderness along deep vein, Additional relevant DVT findings) 
o Confirmatory tests (Compression ultrasonography, Venography, CT Venography, MR 
Venography, Other) 
• If type of VTE is PE: 
o Specific type of PE (Symptomatic PE / Unsuspected PE in a segmental or more 
proximal pulmonary artery) 
o Location of PE (Right Pulmonary Artery / Left Pulmonary Artery, Bilateral 
Pulmonary Artery, Trunk, Right lobar branch / Left Lobal Branch / Bilateral Lobar 
Branches, Segmentary-Subsegmentary artery, Other) 
o If symptomatic, type of symptoms (Breathing difficulties including dyspnea or 
tachypnea, Chest Pain, Cough, Hemoptysis, Tachycardia, Fever, Cyanosis, Additional 
relevant PE findings) 
o Confirmatory tests (CT pulmonary angiography, Pulmonary angiogram, VQ scan, 
Perfusion scan, Echocardio, Other). 
10.5 Medical history and comorbidities 
Data will be summarized for ITT analysis set by treatment group with descriptive statistics. 
Previous diseases are those reported as “Not ongoing” whereas the Concomitant Diseases are those 
reported as “ongoing” in eCRF. 
All verbatim terms will be assigned to a Preferred Term (PT) and will be classified by primary 
System Organ Class (SOC) according to the MedDRA thesaurus version 20.1. 
The following data will be presented: 
1. a default frequency tabulation of patients who exhibited at least one previous disease by 
treatment group; 
2. a frequency table showing the previous diseases by primary System Organ Class and 
Preferred Term by treatment group; 
3. a default frequency tabulation of patients who exhibited at least one concomitant disease by 
treatment group; 
4. a frequency table showing the concomitant diseases by primary System Organ Class and 
Preferred Term by treatment group. 
 
10.6 Previous and concomitant medications 
All medications will be coded using the WHO-DRL Dictionary (DD) B2-format version 2017 and 


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classified according to 3rd level ATC subgroup (Primary therapeutic subgroup) and generic name. 
Concomitant medications are those reported in the eCRF “Concomitant Treatments” form and include 
all medications with start date on or after the study medication start date and all medications taken 
prior to the study entry and still taken after the study medication start date. 
Previous medications are those reported in the eCRF “Concomitant Treatments” form with end date 
before the date of first study drug administration. 
Previous and concomitant medications will be summarized by treatment group for the ITT set. 
Medications started after the date of end of study treatment will be considered as post-study 
treatments and they will be only listed. 
10.7 Study drug 
Data will be summarized by treatment group for mITT set with descriptive statistics. 
Descriptive analyses will be presented by treatment group for: 
• The study drug amount administered (amount dispensed – amount returned); 
• The duration of treatment administration (calculated, in weeks, as (date of last dose – date of 
first dose +1) / 7); 
• Compliance (calculated by the system outside the eCRF). 
 
10.8 Analysis of efficacy 
10.8.1 Analysis of primary endpoint 
Analyses of the primary efficacy endpoint will be performed using the modified intent-to-treat 
(mITT) analysis set, the intent-to treat (ITT) analysis set and the per protocol (PP) analysis set. 
The mITT and the ITT analyses of the primary endpoint will include endpoints that occur at any time 
from randomization until the end of the originally intended treatment period regardless of whether 
subjects were receiving study medication. 
The analysis performed on the mITT population will be considered as the primary whereas the 
analyses performed in the ITT and PP population will be seen as supportive (sensitivity analysis). 
The primary efficacy variable, i.e. the time from randomization to the first recurrent thromboembolic 
event (days), will be analyzed after adjusting estimates for the competing risk of death unrelated to 
VTE. The competing risk analysis will be performed using the SAS procedure PHREG 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). 
Patients without recurrent thromboembolic event will be censored at 6- month (i.e. Day 180). 
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. 
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 


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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 using treatment group, center, symptomatic vs unsuspected VTE and active cancer 
vs history of cancer 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. 
Number and percentage of events of interest, competing events and censored patients will be 
presented as summary of failure outcome. Degrees of freedom (DF), Wald Chi-square and the 
associated p-value derived from the PHREG model will be also presented. 
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. 
10.8.2 Analysis of secondary endpoints 
For the secondary efficacy endpoints, analyses will be performed using the mITT analysis set. 
• The individual components of the primary efficacy outcome (Proximal DVT of the lower 
limbs (symptomatic or unsuspected), DVT of the upper limb (symptomatic), and PE 
(symptomatic or unsuspected): The same competing risk model defined in paragraph 10.8.1 
for the analysis of primary efficacy variable will be employed for the analysis of the time (in 
days) from randomization to the first recurrent event among those included in the primary 
efficacy outcome recurrent (see Paragraph 9.12.1). 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. If neither the event of interest nor a competing event 
occurred within the 6-month follow-up, the patient will be censored at 6- month follow-up. 
• Symptomatic recurrence of VTE: The same competing risk model defined in paragraph 
10.8.1 for the analysis of primary efficacy variable will be employed for the analysis of the 
time (in days) 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. If neither the 
event of interest nor a competing event occurred within the 6-month follow-up, the patient 
will be censored at 6-month follow-up. 
• Composite of primary efficacy outcome plus major bleeding: The competing risk model 
defined in paragraph 10.8.1 for the analysis of primary efficacy variable will be employed for 
the analysis of the time (in days) from randomization to the composite of primary efficacy 
outcome (see Paragraph 9.12.1) 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. If neither the event of interest 
nor a competing event occurred within the 6-month follow-up, the patient will be 


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censored at 6-month follow-up. 
• Death due to any cause (OS): Overall Survival is defined as the time (in days) from 
randomization to the date of death for any cause. OS will be estimated according to Kaplan- 
Meier calculating median, first and third quartiles with the respective 95% confidence 
intervals. Kaplan-Meier plots with a 95% CI will be prepared. OS in the two treatment groups 
will be also compared by means of a Cox’s proportional hazard model with treatment group, 
center, symptomatic vs unsuspected VTE and active cancer vs history of cancer as dummy 
covariates. The apixaban-to-comparator Hazard Ratio will be computed with associated two-
sided 95% confidence interval. Subjects still surviving at the end of the study will be censored 
at the date of the last contact. 
• Composite of primary efficacy outcome plus major bleeding plus death due to any cause: 
Event-free-survival is defined as the time (in days) from randomization to the date of event 
(composite of primary efficacy outcome plus major bleeding plus death due to any cause). 
Event free survival will be estimated according to Kaplan-Meier calculating median, first and 
third quartiles with the respective 95% confidence intervals. Kaplan-Meier plots with a 95% 
CI will be prepared. Event-free-survival in the two treatment groups will be compared by 
means of a Cox’s proportional hazard model with treatment group, center, symptomatic vs 
unsuspected VTE and active cancer vs history of cancer as dummy covariates. The apixaban-
to-comparator Hazard Ratio will be computed with associated two-sided 95% confidence 
interval. Subjects with no events at the end of the study will be censored at the date of the last 
contact. 
• Composite of primary efficacy outcome plus death due to any cause: Event-free-survival is 
defined as the time (in days) from randomization to the date of event (composite of primary 
efficacy outcome plus death due to any cause. 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, center, symptomatic vs 
unsuspected VTE and active cancer vs history of cancer as dummy covariates. The apixaban-
to-comparator Hazard Ratio will be computed with associated two-sided 95% confidence 
interval. Subjects with no events at the end of the study will be censored at the date of the last 
contact. 
• Any fatal or not fatal cardiovascular event: The competing risk model defined in paragraph 
10.8.1 for the analysis of primary efficacy variable will be employed for the analysis of the 
time (in days) 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. Number and percentage of events of interest, competing events and censored patients 
will be presented as summary of failure outcome. Degrees of freedom (DF), Wald Chi-square 
and the associated p-value derived from the PHREG model will be also presented. Subjects 
with no events at the end of the study will be censored at the date of the last contact. 
• All venous thromboembolic events (including splanchnic vein thrombosis and cerebral vein 
thrombosis): The same competing risk model defined in paragraph 10.8.1 for the analysis of 
primary efficacy variable  will  be  employed  for  the  analysis  of  the  time  (in  days) from 


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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. 
Number and percentage of events of interest, competing events and censored patients will be 
presented as summary of failure outcome. Degrees of freedom (DF), Wald Chi-square and the 
associated p-value derived from the PHREG model will be also presented. Subjects with no 
events at the end of the study will be censored at the date of the last contact. 
• Quality of life evaluation (ACTS Scale) (see Appendix 2 of the study protocol): The ACTS is 
a 17-item, patient-reported measure of satisfaction with anticoagulant treatment. It includes 
13 items concerning the burdens of anticoagulant treatment (items 1–12 plus 1 global question 
about burdens) and 4 items concerning the benefits of anticoagulant treatment (items 14–16 
plus 1 global question about benefits). Each of the items is scored on a 5-point Likert scale (1 
= not at all; 2 = a little; 3 = moderately; 4 = quite a bit; 5 = extremely). The Burden score was 
calculated as the sum of questions 1 to 12 subtracted from 60, with a higher score suggesting 
greater satisfaction with treatment. The Benefit score was calculated as the sum of questions 
14 to 16, again with a higher score suggesting greater satisfaction. The Burden subscale can 
take values of 12-60 and the Benefit subscale score ranges from 3 to 15. Questions 13 and 17 
are excluded from the subscale calculations. 
For the Burden score, no imputation on missing data will be applied if ≥ 7 items are 
incomplete; otherwise, the Burden score is calculated as the mean of the complete items score 
x 12. 
For the Benefit score, no imputation on missing data will be applied if ≥ 2 items are 
incomplete; otherwise, the Burden score is calculated as the mean of the complete items score 
x 3. 
Default summary statistics will be presented for each of the two subscales at Visit 5. For each 
of the subscales, a linear effects model will be estimated with treatment group, center, 
symptomatic vs unsuspected VTE and active cancer vs history of cancer as dummy fixed 
effects. The least square means for Apixaban and Dalteparin, with 95% CIs and p-value will 
be presented. The difference between the least squares means for Apixaban and Dalteparin 
will be calculated along the 95% CI and p-value. 


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10.9 Safety analyses 
The analysis of safety will be based on the Safety Population, comparing patients in the two 
randomized arms: apixaban vs. dalteparin. Analysis of safety will include all events recorded during 
the treatment period and up to 30 days after the last study dose intake, 
To assess the bleeding risk associated with the use of either apixaban or dalteparin, we will include 
all bleeding events that occur during the on treatment period, which is the classical period for the 
evaluation of safety. On-treatment bleeding has been defined as occurring during treatment with the 
assigned study drug or up to 72 hours after the last dose intake. 
Concerning bleeding, secondary analyses will be performed: 
1) To determine how apixaban compares to dalteparin therapy based on a reduction in major 
bleeding events over 6 months of therapy; 
2) To determine how apixaban compares to dalteparin therapy in the combined endpoint of 
adjudicated major/CRNM bleeding over 24 weeks of therapy; 
3) To determine how apixaban compares to dalteparin therapy based on a reduction in GI bleeding 
events over 6 months of therapy. 
The number and the percentage of patients with bleeding events as well as the number of events  
will be presented in summary statistical tables. 
10.9.1 Adverse events 
All adverse events recorded during the treatment period and up to 30 days after the last study dose 
intake will be summarized by treatment group with descriptive statistics for the Safety population. 
All adverse events will be assigned to a Preferred Term (PT) and will be classified by primary System 
Organ Class (SOC) according to the MedDRA thesaurus version 20.1. Adverse events will be 
reported on a per-patient basis. This means that even if a patient reports the same event repeatedly 
(i.e. events mapped to the preferred term) the event will be counted only once. In the latter case, the 
event will be assigned the worst intensity and the strongest relationship to the study drug. 
For summaries, the drug-event relationship will be shown as “Related” if relationship with study 
treatment is assessed as “Certain”, “Probable” or “Possible” by the Investigator; otherwise the event 
is considered as “Unrelated”. Missing categories will be considered as related. 
Treatment emergent events, defined as those AEs that start or worsen after the start of 
apixaban/dalteparin and up to 30 days after the last study dose intake, 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. 
The following listing and tables will be presented: 
1) An overview of adverse events with the number of patients who exhibited at least one AE, 
number of adverse events, number of patients who exhibited at least one TEAE, number of 
TEAEs, number of patients who reported at least one related TEAE, number of related TEAEs, 
number of patients who reported at least one treatment-emergent serious adverse event 
(TESAE), number of TESAEs, number of patients who reported at least one related TESAE, 
number of related TESAEs, number of patients who reported at least one AESI, number of 
AESI, number of patients who died, number of patients who temporarily discontinued the 
study drug due to an adverse event, number of patients with premature 


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withdrawal due to an adverse event; 
2) An overview of adverse events with the number of patients who exhibited at least one TEAE 
with DVT as study outcome, number of TEAEs with DVT as study outcome, number of 
patients who exhibited at least one TEAE with PE as study outcome, number of TEAEs with 
PE as study outcome, number of patients who reported at least one TEAE with bleeding as 
study outcome, number of TEAEs with bleeding as study outcome, number of patients who 
reported at least one TEAE with major bleeding as study outcome, number of TEAEs with 
major bleeding as study outcome, number of patients who reported at least one TEAE with 
clinically relevant non-major bleeding as study outcome, number of TEAEs with clinically 
relevant non-major bleeding as study outcome, number of patients who reported at least one 
TEAE with clinically relevant bleeding as study outcome, number of TEAEs with clinically 
relevant bleeding as study outcome, number of patients who reported at least one TEAE with 
myocardial infarction as study outcome, number of TEAEs with myocardial infarction as 
study outcome, number of patients who reported at least one TEAE with ischemic stroke as 
study outcome, number of TEAEs with ischemic stroke as study outcome, number of patients 
who reported at least one TEAE with other venous thrombotic events as study outcome, 
number of TEAEs with other venous thrombotic events as study outcome, number of patients 
who reported at least one TEAE with other arterial thrombotic events as study outcome, 
number of TEAEs with other arterial thrombotic events as study outcome. 
3) Summary of all TEAEs by treatment group, primary System Organ Class and Preferred Term; 
4) Summary of all TEAEs by treatment group, primary System Organ Class, Preferred Term and 
Intensity; 
5) Summary of all TESAEs by treatment group, primary System Organ Class and Preferred 
Term; 
6) Summary of all non-serious TEAEs by treatment group, primary System Organ Class and 
Preferred Term (where PT occurred at a frequency of ≥5%); 
7) Summary of all Related TEAEs by treatment group, primary System Organ Class and 
Preferred Term; 
8) Summary of all Related TESAEs by treatment group, primary System Organ Class and 
Preferred Term; 
9) Summary of all AESI by treatment group, primary System Organ Class and Preferred Term; 
10) Patient Listing of Deaths; 
11) List of TEAEs by patient; 
12) List of TESAEs by patient; 
13) List of Related TEAEs by patient; 
14) List of Related TESAEs by patient; 
15) List of AESI by patient; 
16) List of Patients with Adverse Events Leading to Withdrawal from study drug; 
17) List of Patients with Adverse Events Leading to temporary discontinuation of study drug. 
The number and the percentage of patients with at least one TEAEs by SOC and Preferred Term, 
and the number of events will be presented for the statistical summary from the above points #3 to 


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#9. 
Adverse events with start date before the first study dose intake or after 30 days the last study dose 
intake will be only listed. 
10.9.1.1 Safety study outcomes 
Possible safety study outcomes are: DVT, PE, bleeding, acute myocardial infarction, ischemic stroke, 
other venous thrombotic events, other arterial thrombotic events. 
A frequency table on safety study outcomes will be produced. Details of each category of the study 
outcomes will be summarized by treatment group with default statistics: number and percentage of 
patients with the study outcomes and the number of events reported will be presented. 
Default frequency tabulations (n,%) will be provided for the following categorical variables 
characterizing the safety study outcomes: 
D VT 
• Specific type of DVT (Symptomatic / Unsuspected); 
• Location of DVT (Upper limbs, Vena Cava, Vena iliaca right / Vena iliaca left / Vena iliaca 
bilateral, Right femoral vein / Left femoral vein / Bilateral femoral vein, Right popliteal vein 
/ Left Popliteal vein / Bilateral Popliteal vein, Right Distal vein / Left Distal vein / Bilateral 
Distal vein, Other); 
• If symptomatic, type of symptoms (Pain, Redness, Calf pain of tenderness, Swelling of 
extremities, Tenderness along deep vein, Additional relevant DVT findings); 
• Confirmatory tests (Compression ultrasonography, Venography, CT Venography, MR 
Venography, Other); 
• Event resulting in discontinuation or interruption of patient’s cancer treatment (Yes / No). 
P E  
• Specific type of PE (Symptomatic / Unsuspected); 
• Location of DVT (Right pulmonary artery / Left pulmonary artery / Bilateral pulmonary 
artery, Trunk, Right lobar branch / left lobar branch / Bilateral lobar branch, Segmentary- 
subsegmentary artery, Other); 
• If symptomatic, type of symptoms (Breathing difficulties including dyspnea and tachypnea, 
Chest pain, Hemoptysis, Tachycardia, Fever, Cyanosis, Other); 
• Confirmatory tests (CT pulmonary angiography, pulmonary angiogram, VQ scan, perfusion 
scan, echocardio, other); 
• Event resulting in discontinuation or interruption of patient’s cancer treatment (Yes / No). 
B leeding 
• Single episode / Repetitive bleeding. If repetitive bleeding and main duration of each 
episode known: duration (hours) 
• Major bleeding (Yes / No). 
If major: 
o Decrease in hemoglobin of 2 g/dl (1.2 mmol/L) or more (Yes / No); 
o Transfusion of 2 or more units of packed red blood cells (Yes / No); 


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o Bleeding that occurs in at least one critical site (Yes / No); 
▪ Intracranial (Yes / No); 
▪ Intra-spinal (Yes / No); 
▪ Intra-ocular (Yes / No); 
▪ Pericardial (Yes / No); 
▪ Intra-articular (Yes / No); 
▪ Intramuscular with compartment syndrome (Yes / No); 
▪ Retroperitoneal (Yes / No). 
o Fatal bleeding (Yes / No); 
o Surgical intervention needed (Yes / No). 
• Clinically relevant non-major bleeding (Yes / No). 
If yes: 
o Bleeding compromising hemodynamics (Yes / No); 
o Spontaneous hematoma larger than 25 cm2  (no traumatic cause) (Yes / No); 
o Spontaneous hematomas larger than 100 cm2  (traumatic cause) (Yes / No); 
o Intramuscular hematoma documented by Ultrasonography (Yes / No); 
o Epistaxis requiring tamponade or other medical intervention (Yes / No); 
o Gingival bleeding (Yes / No); 
o Bleeding from venipuncture for > 5 minutes (Yes / No); 
o Spontaneous macroscopic hamtura (Yes / No); 
o Macroscopic hematuria which lasted for more than 24 hours after invasive 
procedures (Yes / No); 
o Hemoptysis requiring endoscopy or other medical intervention (Yes / No); 
o Hematemesis requiring endoscopy or other medical intervention (Yes / No); 
o Spontaneous rectal bleeding requiring endoscopy or other medical intervention (Yes 
/ No). 
I schemic stroke 
• Duration of symptoms (less than 24 hours / more than 24 hours); 
• Assessment by imaging or autopsy (Yes / No). If yes, Non-hemorrhagic / Infarction with 
hemorrhagic conversion); 
• Therapeutic intervention (Yes / No). 
M
 yocardial infarction 
• CK-MB ≥ 2 x ULN (Yes / No / Not available); 
• Troponin T ≥ 2 x ULN (Yes / No / Not available); 
• Troponin I ≥ 2 x ULN (Yes / No / Not available); 
• Total CK ≥ 2 x ULN (Yes / No / Not available); 
• ECG performed (Yes / No). If yes, new significant Q-waves ≥ 0.04 seconds in ≥ 2 
contiguous leads? (Yes / No). 


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O ther venous thrombotic events 
• Clinical sign (Yes / No); 
• Location (splanchnic vein thrombosis, cerebral vein thrombosis, genitourinary vein 
thrombosis, other) 
O ther arterial thrombotic events 
• Clinical sign (Yes / No); 
• Location (carotid artery thrombosis, femoral artery thrombosis, iliac artery thrombosis, renal 
artery thrombosis, retinal artery thrombosis, other). 
Analysis will be performed on the Safety analysis set. 
10.9.2 Laboratory evaluation 
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; 
(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. 
Presentations will use SI Units. 
To convert from the conventional unit to the SI unit, multiply by the conversion factor: 
 
 
Parameter 
Conventional 
Unit 
Conversion 
Factor 
SI Unit 
Hematocrit 
% 
0.01 
Proportion of 1.0 
Hemoglobin 
g/dL 
10 
g/L 
RBC count 
x 106/µL 
0.1 
x 1012/L 
WBC count 
x 103/µL 
1 
x 109/L 
Platelets count 
x 103/µL 
1 
x 109/L 
Creatinine 
mg/dL 
76.25 
µmol/L 
Total Bilirubin 
mg/dL 
17.10 
μmol/L 
Direct Bilirubin 
mg/dL 
17.10 
μmol/L 
Indirect Bilirubin 
mg/dL 
17.10 
μmol/L 
ALT 
U/L 
1 
U/L 
AST 
U/L 
1 
U/L 
ALP (Alkaline Phosphatase) 
U/L 
1 
U/L 


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Partial Prothrombin Time 
(PPT) 
Seconds 
1 
Seconds 
 
10.9.3 Vital Signs 
Vital signs measurement (systolic BP, diastolic BP, heart rate and, for dalteparin group, body weight) 
and their changes from baseline will be summarized by visit and treatment group. Individual vital 
signs measurement will be listed. 
10.9.4 Interim analyses 
Not foreseen. 
10.9.5 Protocol deviations 
An individual data listing of patients who did not satisfy the eligibility criteria will be produced. 
A summary table and an individual data listing of major protocol deviations will be prepared. 
10.9.6 Data and Safety Monitoring Board (DSMB) 
An independent DSMB periodically reviews the study outcomes with all information available 
concerning treatment allocation. A DSMB charter was provided to the board members before the start 
of the study. The DSMB is composed of three expert clinicians with experience in the conduction and 
monitoring of clinical trials. 


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11 Programming Conventions for Outputs 
 
DATES & TIMES 
Depending on data available, dates and times will take the form DDMMMYYYY (i.e. 
01JAN2019) and hh:mm (i.e. 10:35) 
 
SPELLING FORMAT 
English UK 
 
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in that order: 
 
Treatment Group 
For Tables and Listings 
Apixaban 
Apixaban 
LMWH Dalteparin 
Dalteparin 
 
PRESENTATION OF VISITS 
For outputs, visits will be represented as follows and in that order: 
 
Long Name (default) 
Short Name 
Day 
Screening 
V1 
Day -3 or less 
Enrolment 
V2 
Day 1 
Week 4 
V3 
4-week after enrolment 
Month 3 
V4 
3-month after enrolment 
End of study Treatment 
V5 
6-month after enrolment or early 
withdrawal 
End of Study 
V6 
7-months after randomization 
 
LISTINGS 
All listings will be ordered by the following: 
• Treatment group 
• Site ID 
• Patient ID 
• Visit/date/hour (where applicable). 
For listings where non-randomized subjects are included, these will appear in a category after the 
randomized treatment groups labelled “Not Randomized”. 
 
TEXT CASE 
• For titles and column labels, capitalize important words, i.e. nouns, pronouns, verbs, 
adverbs and adjectives but not articles, conjunctions or prepositions 
• All Footnotes will be in sentence case format. 
• All symbols used in body of outputs will be footnoted. 


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12 Partial Date Conventions 
Imputed dates will NOT be presented in the listings. 
 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If start date < study med start date, then not TEAE 
If start date >= study med start date but ≤ study med end 
date+30, then TEAE 
Partial 
If start date < study med start date, then not TEAE 
If start date >= study med start date but ≤ study med end 
date+30, then TEAE 
Missing 
If start date < study med start date, then not TEAE 
If start date >= study med start date but ≤ study med end 
date+30, then TEAE 
Partial, but known 
components show that it 
cannot be on or after study 
med start date 
Known 
Not TEAE 
Partial 
Not TEAE 
Missing 
Not TEAE 
Partial, could be on or after 
study med start date 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date but ≤ study med end 
date+30, then TEAE 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 
are unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date but ≤ study med end 
date+30, then TEAE 
Missing 
Assumed TEAE 
Missing 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date but ≤ study med end 
date+30, then TEAE 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and month 
are unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date but ≤ study med end 
date+30, then TEAE 
Missing 
Assumed TEAE 


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ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS: 
 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post study 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
Missing 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
Partial 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown) and impute stop 
date as latest possible date (i.e. last day of month if day unknown or 31st 
December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
Missing 
Impute start date as earliest possible date (i.e. first day of month if day 
unknown or 1st January if day and month are unknown), then: 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
Missing 
Known 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
Missing 
Assign as concomitant 


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13 References 
Fondazione FADOI, Study Protocol, Protocol no. FADOI 03.2016, Short title The CARAVAGGIO 
Study, Version 3.0 dated 22 May 2018. 
 
SAS Institute Inc., Cary, NC, USA, version 9.4. 
 
Fine JP, Gray RJ. A Proportional Hazards Model for the Subdistribution of a Competing Risk. J Am 
Statist Ass 1999; 94: 496-509 
 
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. 
 
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. 
 
Coleman, C. I., Haas, S., Turpie, A. G.G., Kuhls, S., Hess, S., Evers, T., Amarenco, P., Kirchhof, 
P., Camm, A. J. and on behalf of the XANTUS Investigators (2016), Impact of Switching From a 
Vitamin K Antagonist to Rivaroxaban on Satisfaction With Anticoagulation Therapy: The 
XANTUS-ACTS Substudy. Clin Cardiol, 39: 565–569. doi:10.1002/clc.22565 
 
Hokusai-VTE Investigators, Büller HR, Décousus H, Grosso MA, Mercuri M, Middeldorp S, Prins 
MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P. Edoxaban 
versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 
2013;369:1406-15. 
 
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 
 
EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J 
Med. 2010;363:2499-510 
 
EINSTEIN Investigators. Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary 
Embolism. N Engl J Med. 2012; 366: 1287-97 
 
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. 
 
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 
Guideline on the choice of the non-inferiority margin, Doc. Ref. EMEA/CPMP/EWP/2158/99; 
Statistical principles for clinical trials, ICH harmonised tripartite guideline E9; Points to consider on 
multiplicity issues in clinical trials, CPMP/EWP/908/99. 
 
EMEA, Points to consider on multiplicity issues in clinical trials, CPMP/EWP/908/99 


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14 Tables, line listings and figures shells 
 
The shells of statistical analysis tables, individual data listings and figures to be produced for the 
final statistical analysis of the study data are reported in the document “TLF Shells” version 1.1 
dated 30 October 2019.