Sulodexide (VESSEL®) for the Prevention of Recurrent Venous Thromboembolism in Elderly Patients After a First Episode of Venous Thrombembolism
Phase: PHASE3
Conditions: Venous Thromboembolism, Anticoagulant, Elderly
Sponsor: Arianna Anticoagulazione Foundation

1 
PROTOCOL  
The Jason Study  
Final version 1.0 date 23.10.2018 
 
 
Title of the  Study: 
 
 
The Jason Study:  
Sulodexide  (VESSEL®) for the prevention of recurrent 
venous thromboembolism in elderly patients after a first 
episode of venous thrombembolism  
Code of the Study 
GIASONE (FAAI2.10.2018) 
EudraCT Number: 
2019-000570-33 
Version of Protocol : 
Final Version 1 
Date:  
October 23, 2018 
Supporter: 
The study was supported by a grant from ALFASIGMA;  
ALFASIGMA kindly provided the drug. All data and 
results and all intellectual property rights to the data and 
results derived from the study will be the property of 
Arianna Anticoagulazione Foundation. 
Promoter: 
Arianna Anticoagulazione Foundation 
Via Paolo Fabbri 1/3 
40138 Bologna (BO) 
Phone 051 341471 
Fax 051 343604 
e-mail: segreteria@fondazionearianna.org 
Coordinator Site: 
 
Centro Trombosi e Malattie Emorragiche Humanitas 
Research Hospital Via Alessandro Manzoni 56 20089 
Rozzano (Milano) 
Principal Investigator:  
Dott. Corrado Lodigiani 
Centro Trombosi e Malattie Emorragiche IRCCS Istituto 
Clinico Humanitas - Humanitas Mirasole S.p.A. 
Via Alessandro Manzoni 56 
20089 Rozzano (Milano) 
Phone 02-82244656/4602  
E-mail: corrado.lodigiani@humanitas.it 

2 
 
CONTACT INFORMATION 
Sponsor 
 
Prof. Gualtiero Palareti 
Fondazione Arianna Anticoagulazione 
Via Paolo Fabbri 1/3  
40138 Bologna (BO) 
Tel 051 341471   Fax 051343604 
gualtiero.palareti@unibo.it 
segreteria@fondazionearianna.org 
Pharmacovigilance 
Dott.ssa Elisabetta Bigagli 
NEUROFARBA Dipartimento di Neuroscienze, 
Psicologia, Area del Farmaco e Salute del 
Bambino  
Università degli Studi di Firenze - UniFI  
Viale Pieraccini, 6 - 50139 Firenze 
Tel 055 2758303   Fax 055 2758205 
Mobile 3923176384 
farmacovigilanza-noprofit@neurofarba.unifi.it 
Steering Committee 
 
Prof. Gualtiero Palareti, Prof. Walter Ageno, 
Prof. Angelo Bignamini, Dott.ssa Cristina 
Legnani, Dott. Corrado Lodigiani, Prof. Vittorio 
Pengo, Dott.ssa Daniela Poli, Dott.ssa Sophie 
Testa, Dott. Alberto Tosetto 
Adjudication Committee 
 
Prof. Domenico Prisco, Dott. Davide Imberti, 
Dott. Franco Piovella 
Data Monitoring and Safety Board  
 
Prof. Angelo Bignamini, Dott. Alberto Tosetto, 
Dott.ssa Lorenza Bertù 
Writing Committee 
 
Prof. Gualtiero Palareti, Prof. Walter Ageno, 
Dott. Elisabetta Bigagli, Prof. Angelo 
Bignamini, Dott.ssa Cristina Legnani, Dott. 
Corrado Lodigiani, Prof. Vittorio Pengo, 
Dott.ssa Daniela Poli, Dott.ssa Sophie Testa, 
Dott. Alberto Tosetto 
 
 
Author of study: 
Prof. Gualtiero Palareti 
Presidente Fondazione Arianna Anticoagulazione 
Phone +39 3282279868  
Fax +39 051343604 
gualtiero.palareti@unibo.it  
 
 
 

3 
LISTA DI ABBREVIAZIONI 
 
ACCP  
American College of Chest Physician 
AE 
Adverse event  
ASA 
AcetylSalicylic Acid (Aspirin) 
AVK  
Anti-Vitamin K 
AT 
Anticoagulant Therapy 
BID 
Bis In Die 
CUS 
Compression Ultrasonography 
DM 
Ministerial Decree 
DMSB 
Data Monitoring and Safety Board  
DOAC  
Direct Oral Anticoagulant 
DVT 
Deep Vein Thrombosis 
DVT e/o PE 
Deep Vein Thrombosis and/or Pulmunary Embolism 
eCRF 
Elettronic Case Report Form  
MB 
Major Bleed 
NMCRB 
non-major clinically relevant bleedin 
PE  
Pulmunary Embolism 
FUP 
Follow up 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Regulation  
HR 
Hazard Ratio 
IB 
Investigator’s Brochure 
ICH 
International Council for Harmonisation  
IMPD 
Investigational Medical Product Dossier 
ISTH 
International Society on Thrombosis and Haemostasis 
ITT 
Intent-To-Treat 
mITT 
Modified-ITT 
LMWH 
Low Molecular Weight Heparin 
LSU 
Lipasemic Unit 
NYHA 
New York Heart Association 
NSAE 
Non serius Adverse event 
Post-FUP 
Post Follow Up 
PP 
Per-Protocol Population 
PTS 
Post-Thrombotic Syndrome  
QC 
Quality Control  
RRR 
Relative Risk Reduction 
FSR 
Final Study Report 
RVT 
Residual Vein Thrombosis 
SAE  
serius Adverse event 
SOP 
Standard Operating Procedure 
sPAP 
Systolic Pulmonary Artery Pressure 
SUSAR 
Suspected unespected adverese reaction 
VTE  
Venous ThromboEmbolism 
 
 
 
 
 
 
 

4 
 
 
 
BACKGROUND INFORMATION  
Venous Thromboembolism (VTE) in the elderly population 
VTE is common in the elderly population, with an incidence that may reach 0.5 cases in 100 per 
year in subjects older than 75 years of age (1). Following a first VTE event, an anticoagulant 
therapy of at least 3-6 months (considered as initial and maintenance therapy) is usually prescribed 
for all patients. Following this period, the extension of anticoagulant therapy (extended therapy) is 
suggested in patients with idiopathic VTE or associated with a weak and transient risk factor, aimed 
at avoiding thromboembolism recurrence. The extension of anticoagulant therapy is, however, to be 
decided in relation to the assessment of the risk / benefit ratio on the basis of the individual analysis 
of the risk of VTE recurrence and haemorrhage (2). The risk of VTE recurrence is generally higher 
near the event and tends to decrease with time, while the risk of bleeding in the case of 
anticoagulant treatment remains unchanged over time (or does not increase in relation to the 
increase in age-related underlying risk).  
The high risk of bleeding in the elderly with VTE if treated with anticoagulants or aspirin 
(ASA) over a long period of time. 
In most cases, patients aged 75 years or older who have suffered a first episode of VTE have a 
contraindication to the use of anticoagulant therapy as advanced age is in itself a high-risk factor of 
bleeding. 
The latest American College of Chest Physician - ACCP guidelines (2) suggest evaluating 
individual haemorrhagic risk during an eventual anticoagulant treatment, according to a list of risk 
factors and a consequent score. According to this score, patients older than 75 years of age have a 
high haemorrhagic risk if treated with anticoagulants, and even higher in the presence of other 
morbid conditions among those very common in the elderly (comorbidity, associated 
pharmacological treatments, etc.). For these reasons, at present, patients aged 75 years or older, with 
a first idiopathic VTE event, should discontinue the therapy after a 3-6-month treatment with 
anticoagulant therapy. Sometimes, after having discontinued the anticoagulant therapy, some 
patients are given a low daily dose of ASA (around 100 mg / day). However, according to a recent 
study, this procedure is not recommended, as the administration of ASA implies a low efficacy of 
protection for relapses than the use of anticoagulants, and moreover it is associated with 
considerable haemorrhagic risk, especially in the elderly.  
Difficulty in selecting the elderly with VTE that have a higher risk of recurrence  
Measurement of D-dimer levels is considered good clinical practice today. As suggested by the 
international guidelines (2), in patients with VTE the D-dimer test is used to decide whether to 
permanently discontinue the anticoagulant treatment, if the test is negative, or to decide to continue 

5 
the therapy in those patients with positive D-dimer test considered to be at higher risk of recurrence. 
For this purpose, the D-dimer test is inserted into the predictive scores of the risk of recurrence. 
However, a recent DASH score validation study (4), which includes and gives high value to the D-
dimer result, has shown that the score is not predictive in elderly patients, as this test is almost 
always altered in elderly people.  
Thrombophilia is considered another risk factor. A recent study showed that thrombophilic 
alterations (especially mutations such as factor V Leiden and the prothrombin gene mutation) were 
relatively frequent in elderly people with VTE, with a prevalence of about 14%. However, the 
presence of these thrombophilic alterations was not associated with the risk of VTE recurrence (5).  
The use of direct oral anticoagulant drugs (DOACs) for extended treatment in the elderly 
population  
Recent studies, particularly focused on extensive treatment following VTE, have shown that low 
doses of apixaban (2.5 mg, 2 daily administrations) or rivaroxaban (10 mg, 1 daily administration) 
amongst the whole population treated (6)(3) have allowed both good efficacy results in relation to 
relapses and safety results in relation to the bleeding risk. However, by examining the results of 
these studies, obtained in different population groups relative to age (additional material available in 
publications), it should be noted that: a) in both studies, the population with patients older than 75 
years was very small (between 11 and 13% of the patients included), and b) the results obtained in 
this segment of population, both in terms of efficacy and safety, were certainly lower than those in 
young patients and substantially less satisfactory. 
The use of Sulodexide for the extended treatment of VTE 
The international, randomized, placebo-controlled Sulodexide for the Prevention of Recurrent Deep 
Vein Thrombosis (SURVET) (7) study showed that treatment for 2 years with oral Sulodexide (500 
LSU, BID) in patients (with an average age of 55) who had suffered from a first idiopathic VTE and 
had already undergone an adequate period of anticoagulant therapy, has allowed to reduce the risk 
of thrombotic recurrence by 50% compared to patients treated with placebo, without involving any 
case of major bleeding. A specific scientific literature to demonstrate the absence of haemorrhagic 
effect of the oral administration of Sulodexide is already available (8).  
  
RATIONALE 
Currently, there are no acceptable criteria for identifying elderly patients with a higher risk of VTE 
recurrence. Furthermore, efficacy and safety outcomes in the elderly population are not available 
with regard to the use of DOACs. 
In the light of the SURVET study (7) results, the preventive effect of VTE recurrence (even if lower 
than that achievable with anticoagulant drugs), in association with the absence (or marked decrease) 

6 
of the bleeding risk are factors that justify a specific study on the potential role of extended 
treatment with Sulodexide at the end of a standard period of anticoagulant therapy in elderly 
patients with VTE. 
The study was conceived by creating 3 experimental arms: 
1) Treatment A: Sulodexide (Vessel) 2 capsules of 250 LSU x 2 / day. The choice of this 
dosage is in accordance with that used in the international SURVET study (7) for the 
prevention of relapses of deep vein thrombosis (DVT) and pulmonary embolism (PE). 
2) Treatment B: Sulodexide (Vessel) 1 capsule of 250 LSU and 1 indistinguishable placebo 
capsule x 2 / day. This treatment is justified for the following reasons:  
A) the dose of 250 LSU x 2 / day is the one recommended in the Summary of Product 
Characteristics of Sulodexide for the treatment of post-thrombotic syndrome;  
B) elderly patients are often treated with more drugs a day and administering 4 capsules 
can increase the problems of adherence to therapy;  
C) the daily cost of the drug for future use is reduced. 
3) Treatment C: 2 indistinguishable placebo capsules x 2 / day. In compliance with what has 
been done in the SURVET study and for the safety results obtained.  
Aim of the study 
This study conducted in elderly outpatients (≥ 75 years old at the time of inclusion) ), with at least 
one of the known bleeding risk factor, who had a first episode of lower extremity proximal DVT 
and / or PE, idiopathic or associated with weak or removed risk factors, and who have received 
standard treatment with any oral anticoagulant drug lasting at least 3 months, has the purpose of 
verifying the efficacy and safety of extended treatment with Sulodexide (Vessel®) in the secondary 
prevention of DVT / PE recurrence. 
Objectives  
1) Verify the efficacy of the treatment with two different doses of Sulodexide (Vessel®) 
(treatment A and treatment B) compared to the indistinguishable placebo (treatment C), in 
reducing the incidence of VTE relapses in elderly patients (age ≥ 75 years) who have 
suffered from a recent episode of DVT (proximal lower extremity) and / or PE, by 35% 
compared to placebo. 
2) Verify the safety of the aforementioned therapy, demonstrating non-inferiority compared to 
placebo, with an incidence of major bleeding around 1% (upper confidence limit not > 3%)   
INVESTIGATIONAL PLAN 
Study design 
Phase III, national multicentre, randomised to parallel groups,placebo-controlled, double-blind and 
non-commercial (non-profit) study. 

7 
Study settings 
The study will be conducted nationwide in hospital facilities and / or university facilities with 
outpatients. For the participant centre list, refer to the document "Centre List". 
These centres have been selected as they meet the following criteria:  
• Previous co-authored works  
• Experience in the pathology or condition of the study 
• Previous participations in clinical trials 
• Enrolment capacity 
• Availability to conduct the study 
 
 
Study population 
It is expected to enrol 1,455 consecutive outpatients, aged ≥ 75 years, with at least one of the known 
bleeding risk factor, who have had a first episode of lower extremity proximal DVT and / or PE, 
idiopathic or associated with weak or removed risk factors, and have completed a period of 
anticoagulant treatment (whatever the type of medication used) of at least 3 months. Patients are 
screened when they are still being treated with the anticoagulant. The absence of at least one of the 
conditions listed in the inclusion criteria or the presence of at least one of the conditions listed in the 
exclusion criteria , presented below, determines the exclusion of the patient from further evaluations 
for participation in the study. 
Each centre will enrol on average 30 patients, equally distributed among the three treatment groups 
in balanced blocks. 
 
 

8 
ELIGIBILITY CRITERIA 
Inclusion criteria: 
1) Patients with a first event of proximal lower extremity DVT and / or PE, idiopathic or 
associated with weak or removed risk factors. 
2) Patients aged ≥75 years at the time of enrolment 
3) Pazienti with at lesast one of the known risk factors of bleeding (APPENDIX 1): 
a. Hypertension 
b. Renal failure 
c. Thrombocytopenia 
d. Diabetes 
e. Antiplatelet therapy (ASA maximum 140 mg/die)  
f. Frequent falls (>2 /years) 
g. Nonsteroidal anti-inflammatory drug 
h. Liver  failure 
i. Previous Stroke 
j. Anemia 
k. Poor anticoagulant control  
l. Alcohol abuse 
4) Patients of both sexes. 
5) Patients who at the time of enrolment have already undergone a period of anticoagulant therapy 
(AT, with any medication) of at least 3 months and the therapy has not been suspended for more 
than 30 days. 
6) Patients with no other AT indications.  
7) Patients capable and able to provide informed consent. 
Exclusion criteria: 
1) Patients aged <75 years at the time of the recruitment visit. 
2) "Provoked" index event, which occurred:  
• Within 3 months of surgery or major trauma,  
• Bed Rest > 4 days,  
• Cast / immobility within 3 months. 
3) Index event represented by severe PE, with life threatening risk or treated with thrombolytic 
therapy. 
4) Index event represented by isolated distal DVT or superficial venous thrombosis. 
5) Thrombotic event in  sites other than the deep proximal veins of the lower limbs. 
6) Anticoagulant therapy for less than 3 months at the time of enrolment. 
7) Discontinuation of  anticoagulant therapy for over thirty days at the time of enrolment 
8) Recurrent episodes of DVT ± PE. 

9 
9) Presence of severe post-thrombotic syndrome  (Villalta score >15 or presence ofvenous 
ulcer). 
10) Presence of other clinical conditions requiring anticoagulant therapy. 
11) Active cancer. 
12) Presence of Inferior vena cava (IVC) filter. 
13) Known bleeding diatheses. 
14) Patients treated with antiplatelet drugs other than ASA. The ASA is allowed up to 140 mg / 
day. 
15) All clinical conditions requiring long-term treatment with low molecular weight heparin 
(LMWH). 
16) Presence of Antiphospholipid Antibody Syndrome (according to Sydney criteria) (Appendix 
4) 
17) Presence of serious  thrombophilic alterations  
18) Presence of chronic diseases in acute or active phase (e.g.: inflammatory bowel disease) 
19) Cardiorespiratory failure (NYHA class 3 or 4). 
20) Patients incapacitated or refusing to sign the informed consent. 
21) Patients with life expectancy under 1 year. 
22) Patients residing in a disadvantaged geographical area. 
23) Patient already enrolled in other clinical trials. 
24) Patients with systolic pulmonary artery pressure > 40 mm hg (upper limit for elderly). 
25) Contraindication to Sulodexide (VESSEL®) and Placebo (see the IMPDs) 
STUDY INTERVENTION  
After a first VTE event (proximal DVT of a lower limb and / or PE) and anticoagulant treatment 
(with any medication) for a period of at least 3 months, patients aged ≥ 75 years at the time of 
enrolment, with at least one of the known risk factor for bleeding,  are randomized to receive 
treatment A, treatment B or treatment C for 1 year.  
At each patient will be asked to fill a self-assessment questionnaire for the Villalta score both at the 
beginning of the treatment and at the end. 
 
Prior to enrollment, and after careful consideration of the intended purposes, methods, expected 
benefits and risks of the study, the investigator will obtain informed consent from the patients. 
Patients will discontinue the ongoing anticoagulant therapy (if not already discontinued) and will be 
randomized to take one of the three treatments under evaluation: Treatment A, Treatment B, 
Treatment C. 

10 
It is recalled that before proceeding to the discontinuation of anticoagulant therapy in a patient who 
was affected by VTE, the following investigations are usually suggested: 
A. Compression ultrasonography (CUS)  
Before discontinuing the anticoagulant therapy, as per normal clinical practice, all patients 
with VTE are subjected to the CUS of both lower limbs, with compression of the femoral 
vein in the groin, of the superficial femoral vein in the middle of the thigh, and of the 
popliteal vein (including trifurcation) in the hollow of the knee. The diameter of the residual 
vein thrombosis (RVT) must be measured. The execution of the CUS at the end of 
anticoagulant therapy after VTE is recommended by the guidelines as an indispensable tool 
for the diagnosis of presence or exclusion in cases with suspected recurrent ipsilateral 
thrombosis. 
B. Echocardiographic examination  
For patients who have suffered from pulmonary embolism it is usually suggested to perform 
echocardiography before discontinuation of anticoagulant therapy. This investigation allows 
to identify the possible presence of residual systolic pulmonary hypertension that represents 
a contraindication for the discontinuation of anticoagulant therapy.  
C. Villalta score 
Patients with deep vein thrombosis are usually evaluated upon discontinuation of 
anticoagulant therapy for the presence and level of post-thrombotic syndrome, by applying 
the Villalta score. (Appendix 2) (9) 
 
INVESTIGATIONAL PRODUCT 
The investigational product used in treatment A and B is: 
Vessel®: Sulodexide (Vessel®) is a glycosaminoglycan extract with antithrombotic effect and 
should be administered orally, twice a day throughout the treatment period. 
Pharmaceutical form: soft capsules.  
Approved therapeutic indications: chronic venous ulcers 
Investigational therapeutic indications: prevention of VTE recurrence 
For more information on the investigational product of treatment A refer to the Investigational 
Medicinal Product Dossier (IMPD). 
Placebo 
Indistinguishable placebo is used in treatment B and C. 
Pharmaceutical form: soft capsules. IMPC 
Posology and method of administration in treatment A 
Dosage: 2 soft capsules of Vessel® 250 LSU BID, without food. 

11 
Method of administration: oral route. 
Intervention scheme  
After signing the informed consent, 485 patients are randomised to receive: 
Treatment A: 2 soft capsules of Vessel® 250 LSU BID for 12 months 
Indication of daily dose: Vessel® 1,000 LSU 
Posology and method of administration in treatment B 
Dosage: 1 soft capsule of Vessel® 250 LSU and 1 soft capsule of placebo BDI, without food. 
Method of administration: oral route 
Intervention scheme  
After signing the informed consent, 485 patients are randomised to receive: 
Treatment B: 1 soft capsule of Vessel® 250 LSU and 1 soft capsule of placebo BID for 12 months 
Indication of daily dose: Vessel® 500 LSU 
Posology and method of administration in treatment C  
Dosage: 2 soft placebo capsules BID, without food. 
Method of administration: oral route. 
Intervention scheme  
After signing the informed consent, 485 patients are randomised to receive: 
Treatment C: 2 soft capsules of placebo BID, without food, for 12 months 
Indication of the daily dose.  
 
LABELLING AND PACKAGING 
EXAMPLE BLISTER AND MODEL OF PRIMARY AND SECONDARY LABELLING 
 
EXAMPLE BLISTER 
GIORNO 
 
 
1 
 
 
 
 
2 
 
 
 
 
3 
 
 
 
 
4 
 
 
 
 
5 
 
 
 
 
6 
 
 
 
 

12 
7 
 
 
 
 
8 
 
 
 
 
9 
 
 
 
 
10 
 
 
 
 
 
 
EXAMPLE SECONDARY PACKAGING 
Each box contains 13 blisters 
 
 
 
MODEL LABELLING 
 
PRIMARY LABELLING  
Sponsor Fondazione Arianna Anticoagulazione 
Via Paolo Fabbri 1/3  
40138 Bologna (BO) 
Phone 051 341471 

13 
Study Code GIASONE (FAAI2.10.2018) 
Content: 40 soft capsules, Sulodexide 250 LSU / Placebo 
For oral administration 
Batch Number.: ____________ Code N°: _____________ Kit N°.:_______________ 
 
SECONDARY LABELLING – BOX 1 (kit) 
Sponsor: Fondazione Arianna Anticoagulazione 
Via Paolo Fabbri 1/3  
40138 Bologna (BO) 
Phone 051 341471 
Phone (Only for medical emergency): +XXXXXXXXX Study Code GIASONE (FAAI2.10.2018) 
Content: 40 soft capsules, Sulodexide 250 LSU / Placebo 
The box contains 13 blisters. The blisters contain soft capsules Sulodexide (antithrombotic drug) 250 LSU / 
Placebo  
For oral administration 
Take 2 capsules in the morning and 2 capsules in the evening (about 12 hours apart), away from meals, 
taking the capsules from the same blister and following the number on the blister. 
Batch Number.: ____________ Code N°: _____________ Kit N°.:_______________ 
Kit number: ____________ __ Exspire date: ____________ 
Randomize N.: ______________ (to fill by Investigator) 
Site N°: ________________ (to fill by Investigator) 
Investigator’s Name: ________________ (to fill by Investigator) 
Only for clinical trial. 
Not store at temperatures over 30°C. 
Return the empty packaging and the unused medicine at the study site. Keep out of reach of children. 
 

14 
TREATMENTS 
Treatment initiation 
The beginning of the three treatments under assessment must be scheduled a few days later (at least 
3 days, to allow the elimination of the effect of the previous anticoagulant treatment - especially for 
antivitamin K) and no more than 30 days after the discontinuation of anticoagulant treatment. 
The investigator: 
• Gives the patient the first block of therapy, following the progressive numbering of the 
randomised blocks of therapy and / or placebo entrusted to the centre; the randomisation list is 
computer generated for therapy blocks; transcribes the numbering of the therapy block on the 
treatment labell and in the eCRF and presents the methods of administering and storing the 
medicinal product and returning the remaining boxes and blisters to the patient; 
• Establishes the treatment initiation under assessment, ensuring an interval of at least 3 and not 
more than 30 days compared to the last uptake of the previous anticoagulant treatment; 
• Establishes and agrees with the patient on the date for the 30-day check and the next one when 
the medicinal product will be replenished and the capsules of the returned treatment will be 
counted. 
Check-up at 30 days with confirmation of adhesion  
• The verification can be performed in outpatient or by phone and will be performed after 30 (± 7) 
days from the beginning of the treatment under assessment, and has the purpose of confirming 
the need to adhere to the treatment and to respond to any possible questions / concerns of the 
pacient.  
Follow-up  
• There are 3 follow-up controls, with periodic supply of the medicinal product every 4 months, of 
which the last is the final one (end of the treatment period), without dispensing the medicinal 
product; 
• During each check-up, the investigator will provide the relative count of the capsules reported to 
verify the adherence to the therapy and will record any collateral events that occurred during the 
treatment period; 
During one of the follow-up controls, the investigator may give at his discretion, a questionnaire 
(Appendix 2b) to be filled in by the patient to evaluate the Villalta score. 
It is possible that an unscheduled visit be necessary during the follow-up (also at the request of the 
patient himself / herself).  
After 30 days the conclusion of the study,  it is suggested  that  the investigator makes a control by 
phone to verify the medical condition of the patients. 
Contraindications to the use of Sulodexide:  see the IMPD 

15 
Contraindications to the use of Placebo:  see the IMPD 
 
Investigational product management 
The investigational product and the control product will be adequately manufactured, packaged, 
labelled and will be supplied and distributed free to the hospital pharmacies. 
The investigational product will be accompanied by a regular transport document addressed to the 
pharmacy, containing the product description, quantity, preparation batch, expiry date, any 
particular storage conditions, the reference of the experimental protocol, the department for which 
the experimental drug is intended, the name of the investigator. The pharmacy of the centre will 
deliver the investigational product to the investigator, who will become the consignee upon taken 
over. The consignee or person delegated thereby, is responsible for keeping a special loading and 
unloading register, which must be updated constantly. The pharmacy of the participating centre and 
the investigator will not be able to administer the experimental product to subjects other than the 
trial patients, and will have to ensure that subjects other than the trial staff do not come into contact 
with the investigational drug. As for the residual or expired products, the participating centre will 
use the investigational product provided by the promoter only for the purposes of investigation and 
in accordance with the protocol, undertaking to return the residual investigational products at the 
end of the investigation, at the expense of the promoter, and according to the procedures agreed 
with the promoter. 
Any unused and / or expired product will be withdrawn and destroyed at the end of the study. 
Adherence to the intervention 
Upon check-ups, the investigator will provide the relative count of the capsules reported to verify 
adherence to the therapy. 
Prohibited therapies: 
• Therapy with antiplatelet medicinal products other than ASA. ASA is allowed up to 140 mg / day 
• Long-term treatment with LMWH 
• Treatment with direct oral anticoagulant drugs 
Analysis of the potential benefit / risk ratio for the population 
The risks for the treated population are those related to oral administration of Sulodexide. 
Sulodexide has an antithrombotic action both at the arterial and venous level through a series of 
mechanisms of action such as the inhibition of some factors involved in the coagulation cascade, 
limiting the anticoagulant action. Therefore, an increase in the risk of bleeding could occur in the 
treated population, a risk that is considered to be very low according to scientific literature. 

16 
The potential benefit for patients treated with Sulodexide is related to the decrease of fibrinogen 
levels, to the action on altered blood viscosity in patients with vascular diseases and under 
thrombotic risk.  
Furthermore, a decrease of the thromboembolic recurrence risk has been demonstrated, without an 
increased risk of bleeding.  
The medicinal product has shown particular efficacy in elderly patients. 
Another indirect benefit is the increase in the knowledge of this experimental product in the 
treatment of thrombotic diseases. 
 
WITHDRAWAL OF THE SUBJECTS AND MODIFICATIONS OF THE PROCEDURE 
Premature discontinuation 
The treatment with the investigational product and the control product will be permanently 
discontinued if one of the following events occurs: 
• A serious adverse event that causes premature discontinuation of the treatment 
• The occurrence of a pathology requiring treatment with an anticoagulant drug for an indefinite 
period of time 
• Onset of cancer or other pathology requiring the definitive discontinuation of the 
investigational product and / or control product. 
• Withdrawal of the informed consent. 
• Decision of the attending physician based on the patient's clinical needs 
Temporary discontinuation 
A temporary discontinuation of treatments does not imply premature termination of the study. 
In particular, each treatment may be temporarily discontinued in case of surgery, invasive 
procedure. Treatment will be discontinued during treatment with LMWH. It may be discontinued, 
but not strictly necessary, in the case of minimally invasive manoeuvres (e.g., endoscopy or dental 
extraction). At the end of the discontinuance period, the treatment can be resumed. The period of 
interruption will not imply variations of duration in the observation. A period of temporary 
discontinuance not exceeding 20 days (even non-consecutive) for every 4 months of participation in 
the study is acceptable for the continuation of the study, thus ensuring an overall discontinuance of 
treatment not exceeding 20% of the entire expected duration of treatment. 

17 
Early termination or discontinuance of the study. 
The promoter may interrupt the study at any time on the basis of what will be communicated and 
recommended by the "Data Monitoring And Safety Board" (DMSB) following the assessment of 
the results of the scheduled interim analyses upon the first occurrence of any of these conditions: 
observation of 30 % and 60% of the total events planned for the study, or the achievement of 30% 
and 60% of the patients concluded, the DMSB will inform the promoter if there are conditions of 
evident superiority, evident inferiority or futility, for the entire treatment under assessment or for 
one of the arms in the study, recommending the relative options that could be: early interruption of 
the entire study; early interruption of one of the arms; continuation as expected. Furthermore, the 
DMSB may also recommend – with adequate justification - the redistribution of subsequent cases 
between the study arms or even the change in sample size. In the event of early termination of the 
study or interruption of an active arm, the promoter will promptly notify the competent authorities, 
investigators and ethics committees. Patients will be examined as soon as possible and will continue 
to be followed according to normal clinical practice. 
In case of changes to the distribution of the following cases or of recalculation of the sample size, 
the promoter undertakes to prepare the related amendments to the protocol that will be submitted to 
the competent authorities and to all the ethics committees for approval before applying the proposed 
amendment. 
Deviations from the protocol 
The investigator must not implement any deviations from the protocol or modify it without prior 
agreement with the Fondazione Arianna Anticoagulazione promoter and without prior review and 
approval / favourable opinion of the changes by the Regulatory Authorities and the reference ethics 
committees, except when this is necessary to eliminate an immediate risk for the subjects or when 
the changes imply only logistic or administrative aspects of the study. 
The investigator or his designated person must draw up a document explaining the possible 
deviation from the approved protocol. 
In the event that a change is made to the protocol to eliminate an immediate danger for the 
participants in the trial without prior approval / favourable opinion of the Regulatory Authorities 
and the reference ethics committees, the deviation or change implemented, the reasons thereof and, 
if applicable, the protocol amendments will be sent as soon as possible: 
a) To the Regulatory Authorities and to the reference ethics committees for the revision and 
approval / favourable opinion; 
b) To the sponsor for acceptance. 
Any deviation from the inclusion and exclusion criteria listed above must be approved, in writing 
and on a case-by-case basis, by the investigator and promoter before enrolling the subject. 

18 
Definition of the conclusion of the study 
The study will be concluded for a single patient at 12 months from enrolment (+ 30 days post 
follow-up), except for any premature withdrawal for the reasons stated above. The study will end, in 
general, at the last follow-up visit of the last patient enrolled. However, it is suggested an additional 
observation with a final telephone call 30 days after the discontinuation of therapy to check for any 
events after the definitive discontinuation of the study therapy. The study report will be drawn up 
within the next 12 months. 
Fondazione Arianna Anticoagulazione is the sole owner of all information deriving from the study 
and will be responsible for the decision to terminate it. 
STUDY ENDPOINTS 
Primary endpoints 
• Primary efficacy endpoint:  
- 
cumulative result of: new episodes of venous thromboembolism (proximal DVT and / or 
PE), overall mortality due to VTE 
• Primary safety endpoint:  
- 
incidence of major bleeding (MB), International Society on Thrombosis and 
Haemostasis [ISTH] criterion (10)) (see appendix 1) 
Secondary endpoints  
- 
Secondary efficacy endpoint:Cardiovascular events that involved hospitalization; 
- 
Death from cardiovascular events (myocardial infarction, ischemic stroke). 
• Secondary safety endpoint: 
- 
Cumulative incidence of MB and non-major but clinically relevant haemorrhages  
[NMCRB], (11)) (see APPENDIX 3) 
 
STATISTICAL CONSIDERATION 
Sample size 
Based on available data, the incidence of the primary endpoint (composite of recurrent proximal 
DVT, new PE events and total mortality attributable to TEEs) is estimated to be 13 per 100 patient-
years. Available data (study SURVET [7]) indicate that the relative risk reduction (RRR) of events 
in the high-dose group (500 U b.d.) should be approximately 0.50. It can be expected that the RRR 
in the low-dose group (250 U b.d.) is approximately 0.25. The total relative risk reduction among 
treated subjects can therefore be estimated at approximately 0.38. The expected incidence of events 
among all examined patients should therefore be approximately 8 per 100 patient-years. 
Based on the same information, it is also estimated that the incidence of major bleeding (co-primary 
endpoint) is approximately 1 per 100 patient-years and is not modified by the study treatments. 

19 
Hypotheses 
The hypotheses can be formulated as: 
Efficacy hypotheses: 
a. hierarchically superior hypothesis: 
 regardless of 
dose, where the size of the minimum detectable difference is that indicated above; 
b. hierarchically inferior hypothesis (to be examined if the previous null hypothesis is rejected): 
, where 
 (value expressing the acceptable non-
inferiority limit) is set at 0.045. This indicates that the outcome with the low dose is considered not 
inferior to that of the high dose, if the proportion of events is not greater than that of the high dose 
increased by 4.5 percentage points. 
Safety hypothesis: 
the only hypothesis considered is that the incidence of haemorrhagic events among treated patients 
(regardless of dose) is not superior to that among control and, furthermore, the higher limit of the 
95% confidence interval of incidence does not reach 3%. The hypotheses can therefore be 
expressed as: 
, where 
 is equal to 0.02. This means that 
the outcome among treated is considered not inferior compared to that among controls, in case it 
results in a proportion of haemorrhagic events non greater than that among controls increased by 2 
percentage point and, in any case, with upper limit of the 95% confidence interval not greater than 
3%. 
Multiplicity 
The two co-primary endpoints are not correlated consequently do not influence multiplicity. Two 
other items influence multiplicity: the analyses on the primary efficacy endpoint and the analyses ad 
interim to be supplied to the DMSB. 
a) at least 460 patients per group (460 controls and 920 treated) have 80% power to observe with 
95.2% confidence (alpha = 0.048 two-tailed) a difference of incidence between treated and 
controls equal to approximately 5 percentage points, on the assumption of an incidence among 
controls of 13% [14] 
b) the same number is sufficient (minimum required size: approximately 450 cases per group) to 
have 80% power to observe with 95.2% confidence (alpha = 0.048 one-tailed) the non-inferiority 
of the low-dose vs. the high-dose group, on the assumption of an incidence of events of 

20 
approximately 10% in one group and 6% in the other, accepting a non-inferiority margin of 4.5 
percentage points [15] 
c) the same number is largely sufficient (minimum required size: approximately 330 cases per 
group) to have 90% power to observe with 95.35% confidence (alpha = 0.0465 one-sided) the 
non-inferiority of treated groups combined vs. controls, on the hypothesis of an incidence of 
haemorrhagic events of 1% among controls and accepting a non-inferiority margin of 2 
percentage points [15] and, anyway, accepting an upper limit of the one-sided 95% confidence 
interval of incidence – determined by exact binomial test - not greater than 3%. 
The total sample size should therefore be of approximately 1380 valid cases. Accounting for 
approximately 5% not assessable cases and for the fact that the total number should be a multiple of 
24 – number of cases that can theoretically be assigned to each participating centre to allow 
randomisation blocks of variable size – the total number of subjects to be recruited should be of 
approximately 1450 (theoretically, 1464). 
TIMING OF THE STUDY 
Enrollment 
 
 
 
 
 
24 months 
Duration of Treatment 
 
 
 
12 months 
Maximum duration of the study for each patients 
12 months 
Total duration of the study 
 
 
 
36 months 
First enrolled patients  
 
 
 
September 2019 
Last enrolled patients  
 
 
 
October 2022 
Data Lock 
 
 
 
 
 
April 2023 
Final report 
 
 
 
 
 
September 2023 
 
Inclusion visit to the study 
All patients aged 75 years or older who submit to observation with a first VTE event should be 
evaluated and included in the screening list. Patients who meet the inclusion criteria and who have 
no exclusion criteria must complete a period of at least 3 months of anticoagulant therapy 
(irrespective of the medicinal product used) before being enrolled in the study. 
At screening, the participant centre physician:  
1. Checks the clinical condition of the patient aged 75 years or older ,candidate for the study, and 
checks the general tests (valid within 3 months from the date of the check) that are routine for 
patients who have undergone anticoagulation treatment; 
2. Checks the inclusion and exclusion criteria. In the presence of even one exclusion criterion, 
fills out the patient screening sheet and excludes him / her from the study; 

21 
3. In the event that any exclusion criterion is absent, prior to enrolment, and after adequate 
information about the aims, methods, expected benefits and foreseeable risks of the study, the 
investigator will obtain informed consent from the patients. Patients will discontinue the 
current anticoagulant therapy, if not already suspended, and will be randomised to take one of 
the three treatments  
4. Then keeps the informed consent in the appropriate folder; 
5. Records the required information in the eCRF and writes the study code that connects to the 
patient's name in the file. 
Treatments 
After signing the informed consent, the enrolled patients are randomised to receive: 
• Approximately 485 patients: treatment A: Sulodexide Vessel®, 2 capsules of 250 LSU BID 
for 12 months 
• Approximately 485 patients: treatment B: Sulodexide Vessel®, 1 capsule of 250 LSU and 1 
capsule placebo BID for 12 months  
• Approximately 485 patients: C treatment: 2 indistinguishable placebo capsules BID for 12 
months 
Conduct of the study 
Treatment initiation 
The beginning of treatment should be scheduled a few days later the last assumption of the ongoing 
anticoagulant treatment, especially for VKA 3 days, to allow the removal of the effect of the 
previous treatment, and no more than 30 days after the withdrawal of previous anticoagulant 
treatment. 
The researcher 
1. Gives the patient the first block of therapy, following the progressive numbering of the 
randomised therapy blocks (drug and / or indistinguishable placebo) entrusted to the centre; the 
randomisation list is computer generated for the therapy blocks; transcribes the numbering of 
the therapy block in the eCRF and highlights the methods of administering and storing the drug 
and returning the remaining capsules to the patient; 
2. Establishes the beginning of the treatment under assessment, guaranteeing an interval of at least 
3 and not more than 30 days compared to the last administration of the previous anticoagulant 
treatment; 
3. Establishes and agrees with the patient on the date for the 30-day check and the next check 
when the medicinal product will be replenished and the capsules of the returned treatment will 
be counted. 

22 
First contact 
1. The first subsequent contact will take place after 30 (± 7) days following the beginning of the 
treatment under assessment, and has the purpose of confirming the need for adherence to the 
treatment and responding to any questions / doubts from the pacient;  
2. Any adverse events occurring during the treatment period are recorded  
Follow-up controls 
1. There are 3 follow-up visits, with periodic supply of the drug every 4 months, of which the last 
is the final one (end of the treatment period); 
2. At each visit, the investigator will provide the relative count of the capsules reported to verify 
the adherence to the therapy and will record any adverse events occurring during the treatment 
period; 
3. During any of the follow-up checks, the investigator, at his discretion, will be able to deliver a 
questionnaire to be filled in by the patient to evaluate the Villalta score. The score will be 
included in the eCRF; 
4. A fourth check-up (also by telephone) must be scheduled after  30 days  from the end of the 
therapy period (post follow-up); 
5. At each follow-up visit the appropriate eCRF form must be filled in, as well as for the final 
visit and post follow-up check.  
Unscheduled check-ups 
It is possible that an unscheduled visit be necessary during the follow-up (also requested by the 
patient himself / herself). The visit and its result must be recorded in the eCRF. If the visit shows 
that a primary endpoint has occurred, the visit coincides with the end of the study for that patient, 
and then the end-study section of eCRF must also be filled in. 
End of study  
The end-study section must be filled in for:  
a) Patients who have completed the planned treatment period (including post follow-up control); 
b) Patients for which the unblinding has occurred. 
c) Patients in whom an established  endpoint has occurred; 
d) Patients who withdraw their consent for participation in the study; 
e) Patients who ha signed informed consent and refused the assigned treatment  
f) Patients in whom any circumstances occur that prevent their participation in the study (lost to 
follow-up, patient transfer, death due to causes other than VTE, etc.); 
g) Patients who need to start treatment with VKA or DOAC; 

23 
All events occurring during follow-up and post follow-up, including VTE recurrence, major 
bleeding, non-major but clinically relevant bleeding and death from any cause, will be objectively 
documented and recorded in accordance with current guidelines.  
All events will be awarded by a central adjudication committee (see below) unaware of the type of 
treatment received by patients (investigational product or placebo). In addition, patients are advised 
to immediately contact the enrolling centre upon occurrence of signs or symptoms compatible with 
venous thromboembolism or other complications (such as bleeding episodes). 
Each patient, based on the sequential enrolment order, will receive one of the three planned 
treatments, based on a randomisation list for each of the participating centres. The treatments will 
be identified exclusively through a unique randomisation number and will be distributed in 
randomized blocks. Each treatment will be accompanied by a sealed opaque envelope containing 
the decoding of the treatment assigned for any urgent need for decoding. The opening of the code 
must be reported immediately to the promoter and leads to the patient leaving the study. 
The treatment of patients is discontinued upon the occurrence of: 
▪ 
A primary event, whether related to efficacy (e.g., recurrence of VTE, death) or safety (e.g., 
major haemorrhage);  
▪ 
The patient withdraws his / her informed consent to the study; 
▪ 
The premature discontinuation of the study (see "withdrawal of subjects and changes to the 
procedure"). 
In the case of premature discontinuation without reaching the primary event, the patient is classified 
as censorised at the time of the last valid observation. In such cases, however, the researcher will 
use his best endeavours so as to obtain - except for those who have withdrawn their consent - 
information on the patient's status at the scheduled time for the 2-month check-up following the 
theoretical 12 months of treatment. 
Assignment of the intervention 
The investigator must follow the procedures concerning the assignment of treatments in a 
randomised manner. Please note that the code can be opened exclusively in the circumstances that 
are described in the next paragraph and only in accordance with the protocol.  Furthermore, the 
investigator should promptly document and explain to the promoter the circumstances that led to 
any premature opening of the code (e.g., accidental opening, opening due to a serious adverse 
event).  
The progressive numbering of the randomised therapy blocks (drug or indistinguishable placebo) 
entrusted to the centre is generated by a computer. To avoid the likelihood of predicting the random 
sequence, the details of each block are provided in a separate document not accessible to the 
investigator who recruits patients and assigns the interventions. 

24 
To avoid any selection bias regarding the masking of the assignment, a centralised office distributes 
patients by groups, the investigational drug and the indistinguishable placebo and the numbering 
will be such as not to predict the random sequence.   
Opaque and sequentially sealed envelopes will be used as a mechanism for implementing the 
allocation sequence. The list must remain inaccessible and the envelopes must be opened 
sequentially after enrolling the patient and obtaining the consent. 
The allocation ratio is 2:2:2 . 
The investigator or his delegate is responsible for enrolling patients and assigning them to each 
intervention group. 
 
Masking the treatments and conducting the blind study  
The subjects enrolled in the study, the experimenters, and the members of the Steering Committee, 
Adjudication Committee, Data Monitoring and Safety Board will not be aware of the assignment of 
the 3 treatments following their distribution.  
The unblinding and the possibility of revealing the assignment of the treatment is permitted only in 
the following circumstances: 
▪ The occurrence of an AE for which the investigator needs to unblind the treatment 
▪ The discontinuance of only one of the study arms by the DMSB 
▪ The remodulation of the sample size (with the need to provide a new randomisation for 
subsequent cases) 
Table Timeline of the Study 
Procedure 
Enrolle
ment 
Control  
30 days  
Control   
4 months 
Control  
8 months 
Last 
Control 
12 months 
Eligibility Assessments 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
Medical History 
X 
 
 
 
 
Safety Assessments 
 
 
 
 
 
Physical Examination 
X 
 
 
 
X 
Adherence to treatment 
 
X 
X 
X 
X 
Clinical Drug Supplies 
 
 
 
 
 
Dispense Study Treatment  
X 
 
X 
X 
 
Drug accountability 
 
 
X 
X 
X 
Efficacy End Points 
 
 
 
 
 
Primary 
 
X 
X 
X 
X 
Secondary 
 
X 
X 
X 
X 
Safety End Points 
 
 
 
 
 

25 
Procedure 
Enrolle
ment 
Control  
30 days  
Control   
4 months 
Control  
8 months 
Last 
Control 
12 months 
Primary 
 
X 
X 
X 
X 
Secondary 
 
X 
X 
X 
X 
 
 
 
 
 
DATA MANAGEMENT 
Data collection in electronic case report form 
Upon enrolment, the investigator of the participating centre will collect in the electronic case report 
form (eCRF): 
▪ The personal data, pseudo-anonymised, of the patient inserted 
▪ The general and clinical characteristics of the patient, including laboratory and instrumental 
examinations 
▪ The type, location and characteristics of the thromboembolic event 
▪ The type of treatment for the index event 
▪ Will assign one of the three treatments to the patient and insert the randomisation code into the 
eCRF 
At follow-up checks, the researcher doctor will collect in the eCRF: 
▪ Verification of adherence to therapy  
▪ Recording of adverse events or other complications 
▪ Evaluation of the villata score using a questionnaire (APPENDIX 2B). The delivery of the 
questionnaire is at the discretion of the investigator 
At the post follow-up call, the research doctor will collect in the eCRF: 
• Adverse events or other complications occurring after discontinuation of treatment 
For further details on the data collected, refer to the data collection form submitted together with the 
protocol.  
Fondazione Arianna Anticoagulazione will provide an eCRF to all participating investigators. 
The investigator will access eCRF exclusively for the insertion of the clinical data of his patients, 
which are collected according to this protocol. To safeguard the integrity and confidentiality of data, 
each investigator will be provided with a personal account that will allow access to relevant data on 
the individual centre, blocking any unauthorised intrusion attempt. 

26 
The investigator medical doctor will insert the data on the eCRF, in a strictly anonymised form and 
the subject will be identified only with a code generated automatically with a progressive number of 
insertion. 
The adopted database is mySQL and it will be produced by Softime90 Snc company. 
Data anonymously entered in the eCRF will be recorded and stored in the server of the Arianna 
Anticoagulazione Foundation in Bologna.  
Each access to the eCRF will be managed by personal user name and a password. 
The security system requires that the password be changed at the first access; it requires a length of 
at least 8 characters and provides for a periodic 3-month expiry. 
It is obviously possible to disable the login, if it is deemed necessary by the system administrator. 
Investigators can have full access only to their patient’s data. Every night the data backup is 
automatically performed. 
 
 
Monitoring 
The study monitor, commissioned by Fondazione Arianna Anticoagulazione, will monitor the 
progress of the study remotely, with the aim of ensuring that it is performed, recorded and reported 
in compliance with the protocol, the SOP, the GCP and the applicable regulatory provisions. 
The monitor will contact the centres in advance to schedule the monitoring visit and inform them of 
the documents to be made available for the monitoring day.  
The monitor will show the investigator and his staff the operational details of the protocol and the 
eCRF. 
The monitor will also check the eCRFs and assess its completeness and consistency by remote 
monitoring.  
All entries, corrections and changes must be made by the responsible investigator. Roles and rights 
of the personnel responsible for entering clinical data in the eCRF will be determined in advance. If 
further corrections are necessary, the monitor or data manager will start a query.  
The clinical case researcher will respond to the queries sent. 
During the study, the investigator should allow the monitor to check the progress of the study and 
provide the missing data.  
All the personal data is handled confidentially.  
The Study Monitor will send blind to the Safety Committee the data of the occurred events and all 
the necessary related information for their assessment. 

27 
For any data transfer, all data protection measures will be undertaken (art 32 GDPR 2016/679), 
preventing disclosure to unauthorised third parties and ensuring that confidentiality is maintained at 
all times.  
 
Data monitoring 
Fondazione Arianna Anticoagulazione has established a DMSB to supervise the study. 
The main purpose of the DMSB is the protection of patients enrolled in the study.  
For details on the role and DMSB activity, please refer to the study committee chapter below. 
 
STUDY FEASIBILITY   
We expect that at each participating site at least 30 patients/18 months, in average 18 months will 
be enrolled. Thus, with the participation of 40-50 Italian centers we plan to complete enrolment in 
24 months. With the last patient in completing the study follow-up in 18 months, study completion 
is expected in 3 years.    
 
DATA QUALITY CONTROL 
The promoter ensures that appropriate quality control (QC) procedures are implemented for 
adequate protection of enrolled patients and data quality.  
Professor Angelo Bignamini (Milan), Medical Doctor Alberto Tosetto (Vicenza) and Medical 
Doctor Lorenza Bertù (Vasere) will assist the promoter in the statistical analysis of the study. 
STATISTICAL PLAN 
Populations examined 
In principle, all randomised subjects will be examined for efficacy and safety. Only those subjects 
who, after having signed the informed consent and having been randomised to treatment, refused to 
receive the assigned medication, will be excluded from all analysis and will be classified as 
screening failures. 
The safety analyses (haemorrhages, adverse events, vital signs) shall be performed on all properly 
randomised subjects, excluding only the screening failures. These subjects represent the safety 
population. 
The efficacy analyses will be performed on all properly randomised subjects (Intent-To-Treat 
population; ITT). However, from the ITT population could be excluded, in addition to the screening 
failures, also those subjects presenting violations of the admission criteria, such to make the 
individual case inappropriate for the study. The not assessable cases will equally be excluded, Not 
assessable means those subjects who had been properly followed during the whole observation 

28 
period, had the final evaluation but this evaluation was inconclusive as to the efficacy endpoints and 
cannot be repeated. 
Exclusion of a subject from the ITT population will be decided jointly by the Steering Committee 
and the Adjudication Committee (see below). The Committees will take their decision having 
available the complete CRF for the individual case, but still blinded. 
The resulting population (modified ITT; mITT) will be the population submitted to the efficacy 
analyses.  
The Steering Committee will identify the subjects among the mITT population for whom the 
documentation is available, validated by the Adjudication Committee, demonstrating that one of the 
primary endpoints had been reached, or showing that the planned observation had been concluded 
without any primary event (recurrence, death, severe haemorrhage); who had a compliance with 
treatment of at least 75% of the theoretical amount; and had no protocol violation that the same 
Committee considered major. The analysis of the primary endpoints in this population (per-protocol 
population, PP) will be used as sensitivity analysis for efficacy and safety. 
Descriptive analyses 
Data collected at recruitment will be analysed on the mITT population and, only if necessary, also 
on the safety and PP populations. It is expected that separate analyses will be considered 
appropriate if the difference in number between populations exceeds 10%. 
All collected data will be described as central tendency and dispersion for continuous variables 
(mean with standard deviation and 95% confidence interval if normally distributed; median with 
range interquartile and 95% CI in case of substantial deviation from normal distribution). Nominal 
variables will be described as absolute and relative frequency tables. The results will be expressed 
by treatment group. Formal statistical analysis of the baseline variables is not planned, except for 
those variables that, at the descriptive analysis, will suggest potential differences of clinical 
relevance. In such cases the appropriate tests will be applied: analysis of variance (ANOVA) 
complemented with the Tukey and Dunnet tests for normally distributed continuous variables; 
Kruskal-Wallis test for continuous or pseudo-continuous variables not normally distributed; chi 
square test for nominal variables. 
Primary endpoints analyses 
The primary endpoints of this study are events that can be expressed as frequencies (number of 
events in relation to the observed subjects) and as time to the event occurrence. 
The primary analysis of the primary efficacy endpoint will be the survival analysis according to 
Cox, using as sole covariate the treatment to estimate the hazard ratio, the relevant 95% confidence 

29 
interval and the associated P value. Subsequently, other covariates may be analysed in the same 
model of proportional risk according to Cox, adding to the treatment, if appropriate, the age (in 
decades), sex, the type of index event (PE – alone or associated with DVT – or DVT alone), the 
duration of exposure to anticoagulation (<6 months / ≥6 months), the renal function (glomerular 
filtration rate [GFR] ≥60/<60) the body weight (BMI ≥30/<30) and, if appropriate, the level of 
compliance (<75% / ≥75%). This analysis will be applied to the mITT population and, for what 
applicable, to the PP population. 
The results of the primary efficacy endpoint will also be examined as frequencies. Since it is 
possible that in the mITT population there will be censored cases (those who left prematurely the 
study without having reached an endpoint), procedures will have to be applied to replace the 
missing outcome. Two procedures are anticipated: a) a “worst case” classification, in which all 
censored cases will be classified as failure (endpoint reached); b) if appropriate, attribution to the 
missing outcomes of the outcome seen in the nearest neighbour case, estimated by the propensity 
score computed using the same predictors used for the Cox model, with and without the predictor 
“treatment”. These results will be analysed with the exact Fisher’s test, estimating the relative risk 
and the relevant 95% confidence interval. The analysis will be applied to the mITT and PP 
populations. In this latter, by definition, the missing data replacement will not be required. 
If the comparisons of the primary efficacy endpoint will allow to detect that the treatment, 
regardless of dose, produced a significant effect, then the two doses will be compared, using the 
Cox model for the analysis of the time to the events, and the exact Fisher’s test for the analysis of 
frequencies. These analyses will be performed using the one-sided confidence intervals, in 
accordance with the hypotheses expressed in the sample size calculation. For this analysis the 
reference population will be the PP population, since the estimation of the true effect of different 
doses is affected by the level of compliance. 
The primary safety endpoint (severe haemorrhages) will be analysed in the same way as the primary 
efficacy endpoint, using however one-sided tests in accordance with the non-inferiority hypothesis 
expressed in the sample size calculation. 
 Secondary endpoints analyses 
The secondary endpoints will be examined on the mITT population without replacement of missing 
data, using the same techniques indicated for the analyses of the primary endpoints. 
The compliance is considered a secondary endpoint. The measure of compliance is the proportion 
of presumably consumed medication vs. expected, given the interval between date delivered and 
date returned. Results will be expressed as compliance percent considered as continuous variable, 

30 
and as proportion of subjects with compliance ≥75%. If appropriate, compliance will be compared 
between groups with the analysis of variance and the chi square test. 
Another secondary endpoint is the Villalta score [9], which will be analysed as continuous variable 
and as nominal variable, using the cut-off >5 to identify the post-thrombotic syndrome and the cut-
off >14 to classify the syndrome as severe. The distribution of the continuous variable will be 
analysed with the general linear model for repeated measures, the distribution of the nominal 
variable will be analysed by contingency tables. 
Safety analyses 
Safety analyses will be performed on the safety population, without replacement of missing values. 
The analysis of continuous variables, if appropriate, will compare treatment groups using the 
general linear model for repeated measures if possible, otherwise comparing by ANOVA the 
changes between the last available measurement and the baseline value. 
Adverse events will be tabulated by organ/system, split by treatment groups. No formal analyses 
will be performed, unless the frequency distribution across groups suggests clinically relevant 
differences. In such cases, the specific event will be compared as frequency (subjects with event, 
regardless of the number of events per subject) by groups using the chi square test. 
If appropriate, the number of subjects with at least one event; with at least one serious event; with at 
least one event leading to treatment interruption; with at least one event considered potentially 
treatment-related, will by tabulated by treatment groups and, if needed, compared with the chi 
square test. 
Deaths will be individually described, but the analysis of the relevant frequency was already 
considered among the efficacy endpoints. 
 Interim analyses 
In this study, the periodic assessments will be preformed when reaching the first among the 
following conditions: 
a) 30% and 60% of concluded cases, i.e., when 485 and, respectively, 970 patients will have 
reached the end of the observation, regardless of the number of events, or 
b) 30% and 60% of the primary events (composite of recurrence of proximal DVT, new PE 
episodes, total mortality attributable to TEEs), i.e., when 46 and, respectively, 92 primary events 
will have been confirmed by the Adjudication Committee. 
Impact of interim analyses on the alpha error 
Performing two interim analyses in addition to the final analysis implies and increase of the alpha 
error that, estimated with the O’Brien-Fleming function, imposes to decrease the nominal alpha 

31 
value for the final analysis from 0.05 to 0.048 (two-tailed) for the primary efficacy endpoint [13]. 
This correction was already considered in the sample size calculation. 
Similarly, the critical alpha value (one-sided) to be considered for the final analysis of the safety 
endpoint will change from 0.05 to 0.0465 for the effect of the interim analyses. This correction as 
well was already considered in the sample size calculation. 
SAFETY AND REPORTING 
 
DEFINITIONS 
SERIOUS ADVERSE EVENTS 
A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose:  
- 
results in death 
- 
is life-threatening (defined as an event in which the participant was at risk of death at the 
time of the event; it does not refer to an event which hypothetically might have caused death 
if it were more severe) 
- 
requires inpatient hospitalization or causes prolongation of existing hospitalization (see 
NOTE below) 
- 
results in persistent or significant disability/incapacity 
- 
is a congenital anomaly/birth defect  
- 
is an important medical event (defined as a medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but, based upon appropriate medical and 
scientific judgment, may jeopardize the subject or may require intervention [eg, medical, 
surgical] to prevent one of the other serious outcomes listed in the definition above.) 
Examples of such events include, but are not limited to, intensive treatment in an emergency 
room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do not 
result in hospitalization.)  
- 
Suspected transmission of an infectious agent (eg, pathogenic or nonpathogenic) via the 
study drug is a SAE.  
 
The following hospitalizations are not considered SAEs:  
o a visit to the emergency room or other hospital department < 24 hours, that does not 
result in admission (unless considered an important medical or life-threatening 
event) 
o elective surgery, planned prior to signing consent 
o admissions as per protocol for a planned medical/surgical procedure 
o routine health assessment requiring admission for baseline/trending of health status 
(eg, routine colonoscopy) 
o Medical/surgical admission other than to remedy ill health and planned prior to entry 
into the study. Appropriate documentation is required in these cases. 
o Admission encountered for another life circumstance that carries no bearing on 
health status and requires no medical/surgical intervention (eg, lack of housing, 
economic inadequacy, caregiver respite, family circumstances, administrative 
reason). 

32 
ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of investigational product, whether or not considered related to 
the investigational product. 
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The casual relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and the AE. 
Not related: There is not a reasonable causal relationship between study drug administration and the 
AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship.  
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject 
 
NONSERIOUS ADVERSE EVENT 
A non-serious adverse event is an AE not classified as serious.  
- 
Non-serious Adverse Events (AE) are to be provided in aggregate via interim or final study 
reports as specified in the agreement or, if a regulatory requirement  as part of an annual 
reporting requirement.  
 
SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION – SUSAR 
 SUSAR is defined as an untoward and unintended response to a study drug, which is not listed is 
the applicable product information, and meets one of the following serious criteria: results in death, 
is life-threatening, requires hospitalisation or prolongation of an existing hospitalisation, results in 
persistent or significant disability or incapacity, or is a congenital anomaly or birth defect. 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, 
X-rays, and any other potential safety assessments, whether or not these procedures are required by 
the protocol, should also be recorded as a non-serious or serious AE, as appropriate, and reported 
accordingly.  
 
ADVERSE EVENTS REPORTING 
Serious Adverse Events (SAEs) Collecting and Reporting 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not 
related to study drug, must be collected, including those thought to be associated with protocol-
specified procedures and reported in e-CRF 
 
A SAE report should be completed for any event where doubt exists regarding its status of 
seriousness.  

33 
SAEs must be recorded on the SAE and pregnancy Forms and have to be reported to the 
farmacovigilance referent within 24 hours.  
 
SAE indirizzo mail: farmacovigilanza-noprofit@neurofarba.it 
SAE numero Fax: 055 2758205 
SAE telefono fisso: 055 2758303 
SAE telefono mobile: 392 3176384:  
 
 
Primary and secondary endpoints do not have  to be reported to the farmacovigilance referent 
 
If only limited information is initially available, follow-up reports are required. If an ongoing SAE 
changes in its intensity or relationship to study drug or if new information becomes available, a 
follow-up SAE report should be sent within 24 hours to the Sponsor using the same procedure used 
for transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
 
Non-Serious Adverse Events (NSAEs) Collecting and Reporting 
The collection of non-serious adverse event (NSAE) information should begin at initiation of study 
drug. Nonserious adverse event information should also be collected from the start of a placebo 
lead-in period or other observational period intended to establish a baseline status for the subjects.  
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they 
become serious. Follow-up is also required for nonserious AEs that cause interruption or 
discontinuation of study drug, or those that are present at the end of study treatment as appropriate.  
Nonserious Adverse Events are reported in CRF 
SAE Reconciliation 
The investigator will reconcile the clinical database SAE cases sento to Sponsor Reconciliation will 
occur every six months and once just prior to database lock/Final Study Report (FSR).  The 
investigator will request a safety data reconciliation report  
 
ADMINISTRATIVE ISSUES 
Support of the study 
The study was supported by a grant from ALFASIGMA;  ALFASIGMA kindly provided and 
distributed the treatments.  Participation in the Jason Study  is entirely voluntary and no form of 
remuneration or refund is given to the investigators. 
No profit study  
This study has all the necessary requirements according to the Ministerial Decree of 17 December 
2004 (Art.1, subparagraph 1 and 2) for the definition of "clinical trials designed to improve clinical 
practice as an integral part of health care and not for industrial purposes".  
 

34 
Insurance 
All subjects participating in the study will be covered by an insurance policy taken out by 
Fondazione Arianna Anticoagulazione, which is in accordance with applicable laws and/or 
regulations (D.M. 14 Luglio 2009).   
 
STUDY COMMITTEES 
The scientific integrity of this study will be supervised and publicly assured by four managing 
Committees: Steering Committee, Adjudication Committee, Data Monitoring and Safety Board and 
Writing Committee 
Steering Committee 
The Steering Committee: 
a. supervises the course of the study and ensures that the protocol is carefully followed by each 
participant. To exert this responsibility, the Steering Committee is supported by the Monitor(s); 
is informed of all the monitoring activities and receives – and should take into appropriate 
consideration – the reports of the Data Monitoring and Safety Board as detailed below; 
b. proposes amendments to the protocol to resolve, clarify and implement potential doubts, 
questions or practical difficulties that may onset during the study; 
c. proposes amendments to protocol that may become necessary upon the scientific progress in the 
specific therapeutic segment, to ensure the maintenance of the scientific validity of the study; 
d. solves doubts concerning possible protocol violations, deciding whether individual cases have to 
be classified as minor deviation, major deviation or violation proper and, consequently, whether 
the specific subject is to be included into the safety population only or also into the mITT 
population or event into the PP population. To this aim, the Steering Committee will have 
anonymous and rigorously blinded access to all data relevant to the specific case; 
e. participates to the Writing Committee;F. Assisting the Adjudication Committee in case of 
irremediable disagreement among the members of this committee in expressing their judgment. 
The Steering Committee consists of [Palareti, Ageno, Bignamini, Legnani, Lodigiani, Pengo, Poli, 
Testa, Tosetto] 
Adjudication Committee 
The Adjudication Committee is responsible of validating the efficacy and safety outcomes reported 
by the Investigators, and of classifying the doubtful event of recurrence and/or bleeding as outcome 
or non-outcome. The evaluation by the Adjudication Committee will be blind, with blinded access 
to all data available onto the database for the specific case. The data will be completely anonymous. 
If considered necessary, the Adjudication Committee has the right to request additional information, 
not available onto the database, to the Investigator responsible for the case. All data supplied to the 

35 
Adjudication Committee will anyway be completely anonymous or, where necessary, anonymised 
before being conferred to the Committee. The Investigators participating to the study, for the simple 
fact of accepting this protocol also accept the possibility of receiving such requests for additional 
information and accept to supply what requested, if possible and without prejudice for the respect of 
confidentiality. 
The judgement of the Adjudication Committee is taken by consensus among its member. In case of 
irreconcilable disagreement, the judgement will be deferred to a joint meeting with the Steering 
Committee, in which the decision will be taken by majority. 
The Adjudication Committee is composed of Profs. Domenico Prisco (Florence), Davide Imberti 
(Piacenza) and Franco Piovella (Pavia). 
 
Writing Committee 
The Writing Committee is composed of the Steering Committee, Gualtiero Palareti (Bologna), 
Walter Ageno (Varese) , Angelo Bignamini (Milano), Cristina Legnani (Bologna), Corrado 
Lodigiani (Milano), Vittorio Pengo (Padova), Daniela Poli (Firenze), Sophie Testa (Cremona), 
Alberto Tosetto (Vicenza), complemented with Elisabetta Bigagli (Firenze) and one Investigator 
indicated by each centre having recruited at least 24 patients. 
The Writing Committee: 
a. 
prepares the publication of the main study results; 
b. 
decides additional and subsequent publications of planned and unplanned study results; 
c. 
requests additional statistical analyses of study data in relation to the publications indicated 
above; 
d. 
defines the list of authors for each publication; 
e. 
manages the contacts with the journals and the responses to possible queries for 
clarifications and modifications to the publications sent. 
 
Data Monitoring and Safety Board 
This study will be supervised by a specifically instituted Data Monitoring and Safety Board 
(DMSB). 
The main aim of the DMSB is the patients’ protection, in first instance of those enrolled in the 
study, but also of other patients with the examined disorder. The second responsibility of the DMSB 
is to ensure the integrity of the study, in relation to the compliance with procedures indicated in the 
protocol to guarantee the data credibility. 
The DMSB is composed of Profs. Angelo Bignamini (Milan), Alberto Tosetto (Vicenza), Gualtiero 
Palareti (Bologna) and Lorenza Bertù (Varese). 

36 
To exert its function the DMSB performs periodical evaluations on the data, writes a report with its 
recommendations and submits the recommendations to the Steering Committee. These reports are 
not binding, however, in case the Steering Committee decides not to implement decisions 
recommended by the DMSB, this latter is free to communicate its recommendation to the Ethics 
Committees who approved the protocol. 
 
Procedures 
The DMSB periodically receives from the study monitor a detailed evaluation of: 
- frequency of primary events 
- frequency of serious adverse events 
- frequency of treatment interruptions 
- frequency of subjects lost to follow-up without having incurred into a primary event 
- frequency of potential protocol violations. 
The evaluations presented to the DMSB will, in principle, not be stratified by treatment group. Only 
when the classification by treatment group could imply a decision to interrupt the study or the 
suggestion of a major protocol modification, the results will be stratified by treatment group, always 
blinded as to which treatment. Unblinding, with the attending consequences under the statistical and 
procedural viewpoint, will occur only in the case the DMSB intends to recommend the interruption 
of one study arm only or to recalculate the sample size (with the need to provide a new 
randomisation for the following cases). 
Based on these evaluations, the DMSB decides by majority which recommendation shall be sent to 
the Steering Committee: continue the study as planned in the protocol; implement further 
verifications of adequacy and quality of the applied procedures (to decrease the risks of protocol 
violations and/or facilitate maintaining in the study the recruited patients); interrupt the study for 
manifest superiority or manifest inferiority or futility; interrupt one of the study arms because of the 
of indicated reasons; modify the sample size of the whole study or of one of the arms. 
Interim analysis 
In this study, the periodic assessments will be preformed when reaching the first among the 
following conditions: 
a) 30% and 60% of concluded cases, i.e., when 485 and, respectively, 970 patients will have 
reached the end of the observation, regardless of the number of events, or 
b) 30% and 60% of the primary events (composite of recurrence of proximal DVT, new PE 
episodes, total mortality attributable to TEEs), i.e., when 46 and, respectively, 92 primary events 
will have been confirmed by the Adjudication Committee. 
 

37 
Impact of interim analyses on alpha error 
Performing two interim analyses in addition to the final analysis implies and increase of the alpha 
error that, estimated with the O’Brien-Fleming function, imposes to decrease the nominal alpha 
value for the final analysis from 0.05 to 0.048 (two-tailed) for the primary efficacy endpoint [13]. 
This correction was already considered in the sample size calculation. 
Similarly, the critical alpha value (one-sided) to be considered for the final analysis of the safety 
endpoint will change from 0.05 to 0.0465 for the effect of the interim analyses. This correction as 
well was already considered in the sample size calculation. 
 
DMSB decisional criteria  
Interruption due to manifest superiority  
“Manifest superiority” means that one of the groups (treated regardless of dose, or controls) showed 
at one of the interim analyses a rate of the composite primary efficacy endpoint so largely superior 
compared with the other group, that continuing the study as planned will have very small 
probability to change the result. Furthermore, this result invalidates the principle of equipoise 
among treatments, making unethical the continuation of the study. 
Since the considered hypothesis was two-tailed, the criterion to suggest interrupting the study for 
manifest superiority is that the analysis yields a Z-test value of 3.929 or more at the first interim 
analysis, or of 2.670 or more at the second interim analysis. 
Interruption due to manifest inferiority 
“Manifest inferiority” means that one of the groups (treated regardless of dose, or controls) showed 
at one of the interim analyses a rate of bleedings so largely greater compared with the other group, 
that continuing the study as planned will have very small probability to change the result. 
Furthermore, this result exposes to unacceptable risks one of the groups, making unethical the 
continuation of the study. 
Since the considered hypothesis was one-tailed, the criterion to suggest interrupting the study for 
manifest inferiority is that the analysis yields a Z-test value of 3.393 or more at the first interim 
analysis, or of 2.281 or more at the second interim analysis.  
Interruption due to futility 
“Futility” means that the data collected at the time of the analysis suggest that the study as planned 
will have little probability of reach its primary objectives. This condition can occur because the rate 
of events among controls is less than expected and/or the risk reduction among treated is less than 
expected. If at the first interim analysis the number of events among controls is 14 or less and, at the 
same time, the number of events among treated (regardless of dose) is 19 or more, in absence of 
factor that could justify such deviations from the expected, continuing the study will have very 

38 
small probability of reaching the planned objectives. The same conclusion will be reached if, at the 
second interim analysis, the number of events among controls will be 28 or less and, at the same 
time, the number of events among treated (regardless of dose) will be 37 or more. 
 
Alternative decisions 
In case one the interruption criteria will be reached, or even without reaching one of such criteria 
but in presence of deviations considered relevant by the DMSB in relation to the study objectives, 
the Committee could require that the interim analysis is repeated, stratifying the results by 
treatment group. In case one group presents sufficient evidence of deviating from expected, the 
DMSB could suggest to the Steering Committee: 
- to recalculate the sample size based on the effectively observed incidence of events; 
- to interrupt one the treatment arms based on the deviation of the incidence of events actually 
observed vs. that expected; 
- a combination of both the above suggestions. 
 
ETHICS 
The study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and in compliance with the protocol and ICH-GCP.  
The protocol and any amendments and the informed consent form (or information/non-opposition 
letter, as allowed by local regulations) will have to obtain Institutional Review Board or Ethics 
committee (IRB/EC) approval prior to initiation of the study.  
Informed consent forms 
Participation in this study is entirely voluntary. Informed consent will be obtained in accordance 
with the Declaration of Helsinki, ICH GCP and local regulations. A properly executed, written, 
informed consent will be obtained from each subject prior to entering the subject into the trial.  
Information should be given in both oral and written form and subjects (or their legal 
representatives) must be given ample opportunity to inquire about details of the study.  If 
appropriate and required by the local IRB/IEC, assent from the subject will also be obtained.  If a 
subject is unable to sign the informed consent form (ICF) a legal representative may sign for the 
subject. A copy of the signed consent form will be given to the subject or legal representative of the 
subject and the original will be maintained with the subject’s records. 
Once a patient has been enrolled in the study, he/she may withdraw his/her consent to participate in 
the study at any time without prejudice. Patients will not be entered in the database if the informed 
consent has not been obtained.  

39 
Direct access to source data/document 
The subjects will be informed in writing that representatives of Fondazione Arianna 
Anticoagulazione, EC/IRB, or regulatory authorities may inspect their records to verify the 
information collected, and that all personal information made available for inspection will be 
handled in strictest confidence and in accordance with local data protection laws. If the results of 
the study are published, the subject’s identity will remain confidential. The investigator will retain a 
secure list to enable the patients’ records to be identified. 
Confidentiality 
 All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.  
The promoter of the study will provide the measures to safeguard the subject’s privacy and the 
protection of personal data according to the  EU GDPR 2016/679 
Institutional review board / independent ethics committee 
Before study initiation, the investigator must have obtained written and dated approval from the 
Institutional Review Board/ Independent Ethics Committee (IRB/EC) for the protocol, the patient 
informed consent form (or information/non-opposition document, as allowed by local regulations), 
subject recruitment materials/process (e.g. advertisements), and any other written information to be 
provided to subjects. The investigator or promoter  should provide the IRB/EC with reports, updates 
and other information (e.g. amendments) according to regulatory requirements or institution 
procedures of each country. Protocol amendments, except where necessary to eliminate an 
immediate hazard to subjects, will be issued by Fondazione Arianna Anticoagulazione. Agreement 
from the investigator must be obtained for all protocol amendments and amendments to the patient 
informed consent form (or information/non-opposition document, as allowed by local regulations). 
The IRB/EC must be informed of all amendments and give written approval, which must be 
provided to Fondazione Arianna Anticoagulazione.    
Publication  
 Role of Promoter and Investigators 
The Promoter and the investigators may suggest specific analysis, regarding all or some data of the 
central database. The authorship of the article must provide who proposed the analysis, who 
performed the data analysis, who took part in writing the article. 

40 
Data handling and record keeping 
All data and results and all intellectual property rights to the data and results derived from the study 
will be the property of the Promoter Fondazione Arianna Anticoagulazione according to D.M. 17 
Dicembre 2004. This study is a No Profit Study (D.M. 17 Dicembre 2004, Art. 1, comma 2, lettera 
c). 
Archiving of data 
The investigator should arrange for the archiving of the study documentation file and the raw data 
from the hospital for the longest of the following period of time. At least 7 years after 
completion/discontinuation of the study.  Patient hospital files and other source data should be kept 
for not less than 7 years.   
Final report and publication   
Within 12 months from the completion of the trial and in accordance with ICH-GCP, the promoter 
provides the IRB/IEC with a summary of the trial’s outcome, and the regulatory authority(ies) with 
any reports required. This study will be registered on the site www.clinicaltrials.gov 
(______________________).  All data and results and all intellectual property rights to the data and 
results derived from the study will be the property of Fondazione Arianna Anticoagulazione, who 
may utilize the data in various ways, such as for submission to government regulatory authorities or 
disclosure to other investigators.  All publication or communication (oral or written) will respect the 
international requirements: “Uniforms requirements for Manuscripts Submitted to Biomedical 
Journals”.   
 
 
REFERENCES  
 
1. Heit JA, Spencer FA, White RH. The epidemiology of venous thromboembolism. J Thromb 
Thrombolysis 2016; 41: 3-14. 
2. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST 
Guideline and Expert Panel Report. Chest 2016; 149: 315-52. 
3. Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or Aspirin for Extended Treatment of 
Venous Thromboembolism. N Engl J Med 2017; 376: 1211-22. 
4. Tosetto A, Testa S, Martinelli I, et al. External validation of the DASH prediction rule: a 
retrospective cohort study. J Thromb Haemost 2017; 15: 1963-70. 
5. Siguret V, Emmerich J, Belleville T, et al. Prevalence of Hereditary Thrombophilia in Patients 
Older Than 75 Years With Venous Thromboembolism Referred for Thrombophilia Screening. J 
Gerontol A Biol Sci Med Sci 2015; 70: 977-81. 

41 
6. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous 
thromboembolism. N Engl J Med 2013; 368: 699-708. 
7. Andreozzi GM, Bignamini AA, Davi G, et al. Sulodexide for the Prevention of Recurrent 
Venous Thromboembolism: The Sulodexide in Secondary Prevention of Recurrent Deep Vein 
Thrombosis (SURVET) Study: A Multicenter, Randomized, Double-Blind, Placebo-Controlled 
Trial. Circulation 2015; 132: 1891-7. 
8. Iacoviello L, Dadamo MC, Pawlak K, et al. Antithrombotic activity of dermatan sulphates, 
heparins and their combination in an animal model of arterial thrombosis. Thromb Haemost 
1996; 76: 1102-7. 
9. Villalta S BP, Piccioli A, Lensing AWA, Prins MH, Prandoni P  Assessment of validity and 
reproducibility of a clinical scale for the post-thrombotic syndrome. Haemostasis 1994; 24 (1 
Suppl): 158a. 
10. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic 
medicinal products in non-surgical patients. J Thromb Haemost 2005; 3: 692-4. 
11. Kaatz S, Ahmad D, Spyropoulos AC, et al. Definition of clinically relevant non-major bleeding 
in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-
surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13: 
2119-26. 
12. Benjamini YH, Y. Controlling the false discovery rate: a practical and powerful approach to 
multiple testing. J R Stat Soc Series B Stat Methodol 1995; 57: 289-300. 
13. Reboussin DM, DeMets DL, Kim KM, et al. Computations for group sequential boundaries 
using the Lan-DeMets spending function method. Control Clin Trials 2000; 21: 190-207. 
14. Faul F, Erdfelder E, Lang AG, et al. G*Power 3: a flexible statistical power analysis program 
for the social, behavioral, and biomedical sciences. Behav Res Methods 2007; 39: 175-91. 
15. Zhang E, Wu VQ, Chow S-C, et al. TrialSize: R functions In: in Chapter 
3,4,6,7,9,10,11,12,14,15 2013. 
16. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of 
the classification criteria for definite antiphospholipid syndrome (APS) J Thromb Haemost 
2006; 4: 295–30 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

42 
APPENDIX 1 
Known risk factors of bleeding (adapted from Kearon J et al, CHEST 2016) 
a. Hypertension 
b. Renal failure 
c. Thrombocytopenia 
d. Diabetes 
e. Antiplatelet therapy (ASA maximum 140 mg/die)  
f. Frequent falls (>2 /years) 
g. Nonsteroidal anti-inflammatory drug 
h. Liver  failure 
i. Previous Stroke 
j. Anemia 
k. Poor anticoagulant control  
l. Alcohol abuse 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

43 
 
 
APPENDIX 3 
 
BLEEDING EVENTS 
 
Major bleeding event 
 
A major bleeding event was defined as a bleeding event (as per International Society on 
Thrombosis and Haemostasis guidelines 11), as follows. 
• Acute clinically overt bleeding accompanied by 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, 
intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment 
syndrome, retroperitoneal 
✓ fatal bleeding. 
 
 
Clinically relevant non-major bleeding event 
 
The definition of clinically relevant non-major bleeding (from Kaatz et al. Definition of 
clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and 
venous thromboembolic disease in non-surgical patients: communication from the SSC of 
the ISTH. J Thromb Haemost 2015; 13: 2119-2126) 
 
Any sign or symptom of hemorrhage (e.g., more bleeding than would be expected for a 
clinical circumstance,including bleeding found by imaging alone) that does not fit the 
criteria for the ISTH definition of major bleeding but does meet at least one of the following 
criteria: 
i requiring medical intervention by a healthcare professional 
ii leading to hospitalization or increased level of care 
iii prompting a face to face (i.e., not just a telephone or electronic communication) 
evaluation 
 
 
Minor bleeding events 
 
All acute clinically overt bleeding events not meeting the criteria for either major bleeding 
or clinically relevant non-major bleeding were classified as minor bleeding. 
 
 
Fatal bleeding event 
 
A fatal bleeding event was defined as a bleeding event that the adjudication 
committee determined was the primary cause of death or contributed directly to death.