APIDULCIS: Extended Anticoagulation With Low-dose Apixaban After a Standard Course Anticoagulation in Patients With a First Venous Thromboembolism Who Have Positive D-dimer
Phase: PHASE4
Conditions: Venous Thromboembolism, Anticoagulants
Sponsor: Arianna Anticoagulazione Foundation

 
 
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Protocol APIDULCIS  
Final Version 1.1 in date 16.1.2018 
 
Title of Study: 
 
 
APIDULCIS: Extended anticoagulation with 
low-dose apixaban after a standard course 
anticoagulation in patients with a first 
venous thromboembolism who have 
positive D-dimer 
Code of Study: 
FAA Int1. 7-2017 (APIDULCIS) 
 
Numero EudraCT: 
 
2017-002340-32 
Version of Protocol: 
 
Final Version 1.1 
Date:  
January 16, 2018 
Supporter 
The study was supported by a grant from 
Bristol-Myers Squibb (BMS); Alliance BMS-
Pfizer 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 
Sponsor 
Arianna Anticoagulazione Foundation 
Via Paolo Fabbri 1/3 
40138 Bologna (BO) 
Tel  051 341471 
Fax 051 343604 
e-mail: segreteria@fondazionearianna.org 
Coordinator site 
 
SOD Malattie Aterotrombotiche 
dell’Azienda Ospedaliero - Universitaria 
Careggi di Firenze 
Principal Investigator:  
Dott.ssa Daniela Poli  
SOD Malattie Aterotrombotiche 
dell’Azienda Ospedaliero - Universitaria 
Careggi di Firenze, Largo G. Alessandro 
Brambilla, 3, 50134 Firenze 
Tel   0039 055 7945453 
Fax   00 39055 7946218 
e-mail: daniela.poli.mail@gmail.com 
e-mail polida@aou-careggi.toscana.it 
 
 

 
 
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Title of the study : 
APIDULCIS: Extended anticoagulation with low-dose 
apixaban after a standard course anticoagulation in patients 
with a first venous thromboembolism who have positive D-
dimer 
 
 
Sponsor 
Prof. Gualtiero Palareti 
Presidente Fondazione Arianna 
Anticoagulazione 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
Author of study: 
Prof. Gualtiero Palareti 
Presidente Fondazione Arianna Anticoagulazione 
Tel +39 3282279868  
Fax +39 051343604 
gualtiero.palareti@unibo.it  
 
Prof. Paolo Prandoni 
Dipartimento di Scienze Cardiologiche, Toraciche e Vascolari 
UOSD Coagulopatie - Università di Padova  
paoloprandoni@tin.it

 
 
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Contact information 
Sponsor 
 
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 
Emilia Antonucci 
Fondazione Arianna Anticoagulazione 
Via Paolo Fabbri 1/3  
40138 Bologna (BO) 
Tel 051 341471 
Fax 051343604 
e.antonucci@fondazionearianna.org 
 
 

 
 
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List of abbreviations 
 
ACCP  
American College of Chest Physician 
AE 
Adverse Event 
AVK  
Antagonisti della Vitamina K 
BMI 
Body Mass Index 
CI 
Confidence Interval 
CTscan 
Computerized Tomography scan 
CUS 
Compression Ultrasonography 
CV 
CardioVascolar 
DDU 
D-Dimer Unit 
DOAC  
Direct oral anticoagulant 
DVT 
Deep Vein Thrombosis 
DVT ± PE 
Deep Vein Thrombosis  with or without Polmunary Embolism 
eCRF 
Elettronic Case Report Form  
FEU 
Fibrinogen Equivalent Units 
GCP 
Good Clinical Practice 
HR 
Hazard Ratio 
ICH 
International Council for Harmonisation  
MI 
Miocardial Infarction 
NAE 
Not Serius Adverse Event 
PE  
Polmunary Embolism 
VTE   
Venous ThromboEmbolism  
SAE  
Serius Adverse Event 
sPAP 
Systolic Pulmonary Artery pressure 
VQ scan 
(Pulmonary) Ventilation/ Perfusion scan 
 

 
 
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Indice 
INTRODUCTION ...................................................................................................................................... 7 
BACKGROUND ........................................................................................................................................ 7 
AIM OF THE STUDY ................................................................................................................................. 8 
STUDY DESIGN ........................................................................................................................................ 8 
STUDY POPULATION ............................................................................................................................... 8 
SCREENING OF PATIENTS AND INCLUSION/EXCLUSION CRITERIA ......................................................... 8 
Screening and inclusion of patients ....................................................................................................... 8 
INCLUSION CRITERIA .......................................................................................................................... 9 
Table 1 .......................................................................................................................................................... 9 
Nature of the index VTE events that may be included in the study ............................................................. 9 
EXCLUSION CRITERIA .......................................................................................................................... 9 
Table 2 ................................................................................................................................................ 9 
Exclusion criteria regarding the index event ................................................................................................ 9 
A1) Events usually associated with low risk of recurrence .......................................................................... 9 
A2) Events associated with a very high risk of recurrence or occurrence of life-threatening recurrent 
events ........................................................................................................................................................... 9 
A3) Index VTE events not included in the study ........................................................................................... 9 
Exclusion criteria present at the moment of patients’ screening: ................................................... 10 
Premature Discontinuation .............................................................................................................. 10 
Temporary Discontinuation .............................................................................................................. 10 
STUDY PROCEDURE FOR THE APIDULCIS STUDY .................................................................................. 10 
Eligible patients ................................................................................................................................ 10 
1) CLINICAL INVESTIGATIONS AT SCREENING AND INCLUSION .................................................... 11 
A. 
COMPRESSION ULTRASONOGRAPHY (CUS) AND VILLALTA SCORE .................................................... 11 
B. Echocardiography Examination ................................................................................................. 11 
2) D-DIMER ASSESSMENT ................................................................................................................ 12 
3) RESUMING ANTICOAGULATION: APIXABAN ............................................................................. 12 
Contraindications to use of apixaban (Table 3) .................................................................................... 13 
FOLLOW-UP AND STUDY END-POINTS ................................................................................................. 14 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................................ 14 
STATISTICAL CONSIDERATIONS ............................................................................................................. 17 
Safety end-points and interim analysis ............................................................................................ 17 
PROTOCOL SYNOPSIS ........................................................................................................................... 18 
Study Drug/Treatment: Apixaban ........................................................................................................ 21 
SAFETY AND REPORTING ...................................................................................................................... 23 
1. DEFINITIONS .............................................................................................................................. 23 
SERIOUS ADVERSE EVENTS ......................................................................................................................... 23 
ADVERSE EVENTS ........................................................................................................................................ 24 
NONSERIOUS ADVERSE EVENT ................................................................................................................... 24 
Laboratory Test Abnormalities ................................................................................................................... 24 
Adverse Events of Special Interest ............................................................................................................. 25 
Pregnancy ................................................................................................................................................... 25 

 
 
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Overdose .................................................................................................................................................... 25 
Other Safety Considerations....................................................................................................................... 25 
2. ADVERSE EVENTS REPORTING .................................................................................................. 25 
Serious Adverse Events (SAEs) Collecting and Reporting ........................................................................... 25 
Non-Serious Adverse Events (NSAEs) Collecting and Reporting ................................................................ 26 
SAE Reconciliation ...................................................................................................................................... 26 
DATA COLLECTION DIRECTLY IN ELECTRONIC CASE REPORT FORM ..................................................... 27 
CERTIFICATION OF THE DATA ............................................................................................................... 27 
SECURITY .............................................................................................................................................. 27 
STUDY TIMELINES ................................................................................................................................. 27 
STUDY FEASIBILITY ............................................................................................................................... 27 
DATA QUALITY CONTROL ...................................................................................................................... 28 
ETHICAL CONDUCT OF THE STUDY ....................................................................................................... 28 
DIRECT ACCESS TO SOURCE DATA/DOCUMENT ................................................................................... 28 
CONFIDENTIALITY ................................................................................................................................. 28 
INFORMED CONSENT FORM ................................................................................................................ 28 
INSTITUTIONAL REVIEW BOARD / INDEPENDENT ETHICS COMMITTEE.............................................. 29 
DATA HANDLING AND RECORD KEEPING ............................................................................................. 29 
ARCHIVING OF DATA............................................................................................................................. 29 
FINAL REPORT AND PUBLICATION ....................................................................................................... 29 
NO PROFIT STUDY ................................................................................................................................ 30 
Study Promoter .................................................................................................................................... 30 
Coordinator Site ................................................................................................................................... 30 
Principal Investigator ............................................................................................................................ 30 
INSURANCE .......................................................................................................................................... 30 
REFERENCES ......................................................................................................................................... 31 
APIDULCIS STUDY ................................................................................................................................. 32 
APPENDIX 1 .......................................................................................................................................... 32 
TIMING OF D-DIMER MEASUREMENTS ............................................................................................... 32 
D-dimer should be measured at the following time points after anticoagulation is stopped. ............ 32 
T0 
= during anticoagulation ........................................................................................................... 32 
T1    
= 15±2 days after anticoagulation is stopped ........................................................................... 32 
T2  
= 30±4 days after anticoagulation is stopped ........................................................................... 32 
T3  
= 60±5 days after anticoagulation is stopped ........................................................................... 32 
PREDEFINED CUT-OFF LEVELS FOR NEGATIVE/POSITIVE ..................................................................... 33 
D-dimer cut-off levels (ng/ml) for males or females (aged 18-75 years) ............................................. 33 
APPENDIX 2 .......................................................................................................................................... 34 
OUTCOME DEFINITIONS ....................................................................................................................... 34 
VENOUS THROMBOEMBOLISM (VTE) .................................................................................................. 34 
 
 

 
 
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INTRODUCTION  
 
The APIDULCIS is a prospective cohort study which aims at optimizing the long-term and extended 
management of patients with venous thromboembolism (VTE), including patients at a first episode 
of proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE), whose pathogenesis is 
either unknown (unprovoked VTE) or associated with weak risk factors for thrombosis, with the help 
of a predefined algorithm. 
 
BACKGROUND 
The cumulative incidence of recurrent symptomatic VTE events at 10 years after stopping 
anticoagulation is approximately 50% after a first unprovoked VTE, and about 20% after a provoked 
event 1. These figures are not related to the duration of anticoagulant treatment, the long-term rate 
of recurrent events after discontinuing anticoagulation being virtually unmodified after 3,6,12 and 
24 months of treatment 2. 
 
The latest ACCP international guidelines suggest an indefinite duration of anticoagulation in all 
patients after an unprovoked event, provided they are at low or moderate risk of bleeding 3. 
However, the rate of fatal bleeding while on indefinite treatment is comparable to that of fatal PE in 
patients in whom anticoagulation is discontinued 4, and the case-fatality rate of major bleeding is 
higher than that of symptomatic recurrent events 5. It should also be pointed-out that the ACCP 
guidelines propose a score to assess the individual bleeding risk which evaluates as at high bleeding 
risk subjects aged > 75 years. All these evaluations stem from studies in whom vitamin K antagonists 
(VKA) had been used for the secondary prevention of VTE disorders. Accordingly, most physicians do 
not accomplish these recommendations 6. In clinical practice, prolonging indefinitely anticoagulation 
beyond the first months appears a reasonable choice only in some categories of patients, including 
those with a personal or familiar history of VTE, those with known major thrombophilic disorders 
(such as deficiencies in the natural anticoagulants or the antiphospholipid syndrome), those with 
severe presentations (such as life-threatening PE) and those with a cava filter. 
 
New scenarios have recently been offered by the use of the novel direct oral anticoagulants 
(DOACs), both for initial and standard anticoagulation course and for extended treatment. In 
particular for the last clinical scope, low-dose apixaban (2.5 mg BID) 7, aspirin (100 mg OD) 8, and 
sulodexide (500 mg BID) 9, proved effective (though with different extent) and with better safety 
results than expected by using VKAs. Indeed, randomized placebo-controlled clinical trials conducted 
in patients with unprovoked VTE who had received 3-12 months of conventional anticoagulation 
showed a reduction of the incidence of recurrent events of approximately 80% with low-dose 
apixaban 7, 35% with aspirin 8 and 50% with sulodexide 9, respectively. 
 
Finally, in the DULCIS management study 10 it was shown that in patients with an unprovoked (or 
associated with a weak risk factor) symptomatic episode of proximal DVT and/or PE who had 
received a standard course of anticoagulation with VKA, serial D-dimer measurement in combination 
with the assessment of residual thrombosis in the deep leg veins is suitable in clinical practice to 

 
 
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distinguish VTE patients who have low recurrence risk (annual rate, 3.0%) and can discontinue 
anticoagulation from those who have, in contrast, a high risk of recurrence and deserve extended 
anticoagulation. It was also found that after 12 months of anticoagulation the rate of recurrent 
events was not different in subjects with or without residual vein thrombosis. In the DULCIS study, 
however, the rate of major bleeding complications in those who resumed VKA anticoagulation was 
substantially high (3.7%; 2.3% annually). In addition, the number of patients older than 70 and that 
of patients with isolated PE was not high enough to yield robust conclusions. 
The use of D-dimer assessment after anticoagulation is stopped has also been suggested by the 
latest ACCP guidelines 3 as a tool to guide deciding on extended anticoagulation or not. 
 
AIM OF THE STUDY 
The main aim of this prospective cohort study is to assess the efficacy and safety of a management 
procedure to decide on giving or not an extended anticoagulation (administering apixaban 2.5 mg 
BID) to outpatients with a single episode of proximal DVT of the lower limbs and/or PE who had 
received 12-18 months anticoagulation (whatever the anticoagulant drug used). The study seeks to 
assess whether a management procedure involving D-dimer testing assessment can identify a subset 
of subjects at low risk of recurrence in whom an extended anticoagulation can be safely avoided. 
 
STUDY DESIGN   
Phase IV, multicenter, national, prospective cohort study    
 
STUDY POPULATION  
The study includes outpatients with a single episode of venous thromboembolism (VTE), at a first 
episode of proximal deep vein thrombosis (DVT) and/or pulmonary embolism (PE), whose 
pathogenesis is either unknown (unprovoked VTE) or associated with weak risk factors for 
thrombosis, who had received 12-18 months anticoagulation (whatever the anticoagulant drug 
used). 
 
 
SCREENING OF PATIENTS AND INCLUSION/EXCLUSION CRITERIA 
 
Screening and inclusion of patients 
All consecutive patients who have experienced a single episode of proximal DVT of the lower limb 
and/or PE that was unprovoked or associated with a risk factor that was removed (see Table 1), and 
have completed 12-18 months of anticoagulation (whatever the drug used) will be screened by the 
participant centers when they are still being treated with anticoagulants and the screening form 
completed.  
Those who do not have any of the exclusion criteria listed in Table 2 will be invited to participate in 
the APIDULCIS study (DVT- or PE-subgroup study).  

 
 
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INCLUSION CRITERIA 
Table 1  
 
Nature of the index VTE events that may be included in the study 
 
 Event that was unprovoked or associated with a risk factor that was removed  
 Events that occurred in association with one or more risk factors that are no longer present 
 Female and male patients of all ethnicity 
 Signature of informed consent 
 Age older than 18 or younger than 75 years 
 Patients who completed 12-18 months of anticoagulation (whatever the drug used) 
 
EXCLUSION CRITERIA 
Table 2 
Exclusion criteria regarding the index event 
A1) Events usually associated with low risk of recurrence 
 
 DVT/PE occurred within 3 months from major surgery or major trauma 
 Isolated Distal DVT (thrombosis of calf veins)  
A2) Events associated with a very high risk of recurrence or occurrence of life-threatening 
recurrent events 
 
 PE episode with shock or life-threatening 
 Isolated PE with a systolic pulmonary artery pressure > 60 mmHg at presentation 
 DVT/PE associated with active cancer, antiphospholipid syndrome or long-standing medical 
illnesses 
 More than one idiopathic event 
 
 For the patients listed in A2 the risks of recurrence or of seriousness of recurrent events are 
too high to accept an interruption of anticoagulation, even if temporary. According to the 
present management protocol these patients should be invited to continue the anticoagulant 
treatment. Participants in the APIDULCIS study are however recommended to follow-up 
these patients, taking note of the decision about anticoagulation and of their clinical history 
during follow-up.  
 
A3) Index VTE events not included in the study 
 All VTE events that occurred in different sites than deep veins of the lower limbs or 
pulmonary arteries  

 
 
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Exclusion criteria present at the moment of patients’ screening: 
 More documented unprovoked VTE episodes  
 Pregnancy or puerperium or planning to become pregnant during the following 18 months  
 Severe post-thrombotic syndrome (=> 15 points at the Villalta score) 
 Solid neoplasia or blood disease in active phase or requiring chemotherapy/radiotherapy 
 All the clinical conditions requiring prolonged treatment with LMWH   
 Presence of overt, active chronic diseases (i.e. inflammatory bowel disease) 
 Known serious thrombophilic alterations 
 Any absolute contraindication to anticoagulant therapy 
 Any contraindication to apixaban (as per local SmPC) 
 Presence of antiphospolipid syndrome 
 Presence of cava filter  
 Concomitant conditions (such as atrial fibrillation) requiring indefinite anticoagulation  
 Severe cardio-respiratory insufficiency (NYHA 3 or 4) 
 Life expectancy shorter than 1 year 
 Refuse interruption of anticoagulation to perform serial D-dimer assessment 
 Duration of anticoagulant treatment over 18 months 
 Geographically inaccessible location  
 Inability or refusal to give consent  
 Patients already enrolled to other non observational clinical trials 
 
Premature Discontinuation  
Study treatment will be permanently stopped if any of the following events occur:  
 pregnancy. Women of childbearing potential must perform a pregnancy test in case of 
delayed menstruation and stop treatment immediately in case of positive result.  
 a serious adverse event (SAE) warranting premature termination. 
 Withdraw of given informed consent 
 Occurence of a condition requiring indefinite anticoagulant treatment    
 Occurence of cancer or other conditions requiring Apixaban stopping 
 
Temporary Discontinuation  
Study treatment can be temporarily stopped in case of surgery, invasive procedures or non-major 
but clinically relevant bleeding 
 
STUDY PROCEDURE FOR THE APIDULCIS STUDY  
 
Eligible patients 
The APIDULCIS study includes two pre-specified types of patients: 
The DVT patients, with proximal DVT, alone or associated with PE) 
The PE patients, with isolated PE without any DVT) 

 
 
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Patients are screened for inclusion in the study during anticoagulation and only when they have 
completed 12-18 months of anticoagulant treatment·  
1) CLINICAL INVESTIGATIONS AT SCREENING AND INCLUSION 
A. COMPRESSION ULTRASONOGRAPHY (CUS) AND VILLALTA SCORE  
 
DVT-patients 
Patients with proximal DVT, alone or associated with PE, who have the inclusion and no one of the 
exclusion criteria are invited to proceed to the bilateral ultrasound examination of the common 
femoral vein, superficial femoral vein (at the mid-thigh) and popliteal vein (involving the 
trifurcation). The diameter of RVT at compression (or no RVT) should be measured and reported in 
the forms. Patients should also be examined according the Villalta score and excluded from further 
participation in the study if the score is => 15 points. Whatever the result of CUS, and if the Villalta 
score is < 15 points, the patients are invited to participate in the APIDULCIS DVT-subgroup study and 
to sign informed consent. These patients are invited to undergo to the serial D-dimer testing. 
Isolated PE-patients  
Patients who as index event presented with an isolated PE (not associated to any deep vein leg 
thrombosis), who have completed 12-18 months anticoagulation, whatever the anticoagulant drug 
used, and who do not have any of the above listed exclusion criteria, are eligible for inclusion in the 
PE-subgroup study.  
 
Patients should receive a bilateral proximal CUS at screening; if CUS gives completely negative 
results (no signs of previous DVT) they are asked to participate in the PE-subgroup study and to sign 
the informed consent. Those with ultrasound signs of a previous leg DVT cannot be included in the 
Isolated PE-Subgroup, but can be included in the DVT-Subgroup study.  
 
B. Echocardiography Examination 
 
Patients who had suffered of PE (either isolated or associated with DVT) should receive an 
echocardiography investigation before deciding the suspension of anticoagulation in order to 
identify the possible presence of a pulmonary hypertension. Patients with a systolic pulmonary 
artery pressure (sPAP) above the following cut-off limits (> 35mmHg, or > 40mmHg in elderly or 
obese patients) are recommended to continue anticoagulation and to undergo to cardiological 
examination; they are excluded from further progression in the study. 
 
C. Perfusional Pulmonary Scintigraphy (not mandatory) 
 
This assessment, if available, will be used to record the possible persistence of residual 
thrombotic occlusion in pulmonary arteries and verify its relationship with recurrence during 
follow-up. All patients, however, will undergo to serial D-dimer assay to decide on 
interruption or extension of anticoagulation independently on presence/absence of residual 
arterial thrombi.   

 
 
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2) D-DIMER ASSESSMENT  
 
Patients included in both Subgroups of the study are invited to undergo D-dimer measurements.  
They are informed that:  
a) the cut-off value used in the study can be different than the limit values shown in the laboratory 
reports of the tests;  
b) in case D-dimer assay would give a positive result (above the study cut-off value established for 
the used assay) they would be advised to continue anticoagulation or, if anticoagulation has already 
been stopped, to resume anticoagulant treatment by assuming in both cases the novel direct oral 
anticoagulant drug apixaban (Eliquis) 2.5 mg BID, provided by the study, that is associated with a low 
risk of bleeding, according to the currently available scientific literature. The patients will then 
receive a serial determination of D-dimer assay (a maximum of four determinations in case of 
negative results) by using the routinely locally adopted method assay (provided it is one of those 
listed in Appendix 1).  
 
The D-dimer measurement should be performed at the moment of patient screening, when patients 
still assume their anticoagulant treatment (T0), and at 15±2 days (T1), 30±4 days (T2), and 60±5 (T3) 
days after their anticoagulant treatment has been stopped.  
 
Patients with a positive D-dimer assay who may refuse to continue anticoagulation will be followed 
for the next 18 months.  
 
Patients with positive D-dimer results at T0 (see Appendix 1 for D-dimer cut-off levels according sex) 
are offered to continue anticoagulant treatment by shifting to receive apixaban (Eliquis) 2.5 mg BID. 
If they accept to be treated with apixaban they are included in the study and followed-up for 18 
months; if they decide to continue their current anticoagulant treatment (different than apixaban 
2.5 mg BID) they are excluded from further participation in the study. Patients with negative D-dimer 
result at T0 are invited to stop assuming their anticoagulant therapy and continue on serial D-dimer 
measurements. At the first positive D-dimer result in serial testing, they are invited to resume 
anticoagulation by assuming apixaban (Eliquis) 2.5 mg BID.  
 
Patients with persistently negative results of the four serial D-dimer measurements, are invited to 
stay definitively without anticoagulation and discouraged from resuming any antithrombotic drug 
for secondary VTE prevention. 
 
 
3) RESUMING ANTICOAGULATION: APIXABAN 
 
At the first positive D-dimer results (during anticoagulation or after its temporary withdrawal) the 
patients are invited to assume Eliquis (apixaban) 2.5 mg twice daily (kindly provided by Alliance 
BMS-Pfizer), and continue this therapy for the following 18 months. Patients who were treated with 

 
 
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VKA (warfarin) will be invited to stop warfarin for 3 days and then start with apixaban 2,5 mg BID 
(according to apixaban SmPC). Those patients who are treated with another direct oral 
anticoagulant will start apixaban treatment at the next scheduled dose. 
The choice of giving apixaban at the dose reported above is based on the results of the AMPLIFY-
Extension study 7 that enrolled symptomatic DVT or PE patients who had completed 6 to 12 months 
of anticoagulation therapy and for whom there was clinical equipoise regarding the continuation or 
cessation of anticoagulation therapy. In that study the included patients were randomized to receive 
apixaban 5 mg BID or 2.5 mg BID doses, or placebo for the following 12 months. Treatment with 
apixaban 5 mg BID and that with 2.5 mg BID doses were superior to placebo in prevention of 
symptomatic, recurrent VTE or death from any cause (p< 0.001 for both comparisons). The rate of 
major bleeding was similar in the three treatment groups at 0.5% (n = 4) with placebo, 0.2% (n = 2) 
with apixaban 5 mg and 0.1% (n = 1) with apixaban 2.5 mg. In addition, the rate of major or clinically 
relevant non-major bleeding was 2.7% in the placebo group, 4.3% in the apixaban 5 mg group and 
3.2% in the apixaban 2.5 mg group.  
Other new direct oral anticoagulants have been investigated for extended treatment in patients with 
VTE after an initial period of standard anticoagulation. However, dabigatran and rivaroxaban were 
found to be associated with a higher rate of major and non-major clinically relevant bleeding than 
placebo.  
Based on these data, in the APIDULCIS study it was decided to give apixaban (Eliquis) 2.5 mg BID to 
patients who deserve resuming anticoagulation according to the management procedure adopted in 
the study.  
 
 
Contraindications to use of apixaban (Table 3) 
 
 Hypersensitivity to the active substance or to any of the excipients listed in the RCP of 
apixaban (section 6.1.) 
 Active clinically significant bleeding. 
 Hepatic disease associated with coagulopathy and clinically relevant bleeding risk. 
 Lesion or condition if considered a significant risk factor for major bleeding. This may include: 
 current or recent gastrointestinal ulceration, presence of malignant neoplasms at high risk of 
bleeding, recent brain or spinal injury, recent brain, spinal or ophthalmic surgery, recent 
intracranial hemorrhage, known or suspected esophageal varices, arteriovenous 
malformations, vascular aneurysms or major intra-spinal or intracerebral vascular 
abnormalities; 
 concomitant treatment with any other anticoagulant agent e.g., unfractionated heparin 
(UFH), low molecular weight heparins, heparin derivatives (fondaparinux, etc.), oral 
anticoagulants (warfarin, rivaroxaban, dabigatran, etc.) except under specific circumstances 
of switching anticoagulant therapy or when UFH is given at doses necessary to maintain an 
open central venous or arterial catheter. 
 
The patients with one of the absolute contraindications to Eliquis are invited to resume 
anticoagulation using a different anticoagulant drug.  
 

 
 
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FOLLOW-UP AND STUDY END-POINTS 
 
All patients included in the study, a) those with persistently negative D-dimer who stopped 
anticoagulation, b) those with positive D-dimer who continued or resumed anticoagulant treatment 
by assuming apixaban 2.5 mg BID, and c) those with positive D-dimer who may refuse to assume 
apixaban as well as any other anticoagulant or antithrombotic agent for secondary VTE prevention, 
will be followed up for at least 18 months after recruitment in the study. They will be examined or 
interviewed telephonically every 3-6 months in order to assess their health conditions and to check 
the occurrence of events. All primary events occurring during the follow-up, including objectively 
proven recurrent VTE, major or clinically relevant non-major bleedings and deaths from any cause 
will be objectively documented according to widely accepted guidelines and recorded. All the events 
will be adjudicated by a central adjudication committee. All the patients are invited to immediately 
refer to the enrolling center at the appearance of signs or symptoms compatible with venous 
thromboembolism or other complications (such as bleeding episodes).  
 
 
Primary efficacy end-point: the composite of confirmed recurrent VTE and VTE-related death 
occurring during follow-up in all included patients  
 
Primary safety end-point: major bleeding 11 complications occurring during the follow-up period in 
all included patients 
 
Secondary efficacy end-points: other thromboembolic events, (severe) post-thrombotic syndrome 
(at the end of follow-up period patients with DVT as index event should receive a final evaluation of 
the Villalta score),  
 
Secondary safety end-points: clinically relevant non major bleeding complications, overall mortality 
 
All suspected outcome events and deaths will be evaluated by a central adjudication committee 
whose members will be unaware of patient name, D-dimer testing results, type of management or 
enrolling center. 
 
STUDY ASSESSMENTS AND PROCEDURES 
 
This study is divided into 2 main periods: 
1. Screening: After obtaining written informed consent, all potential patients will complete the 
screening visit. If fulfilling the eligibility assessments, they will be enrolled. Evaluation of 
results of D-dimer laboratory results, if the value is positive the patients are invited to 
continue anticoagulant treatment by assuming Apixban 2,5 mg BID for 18 months. Patients 
with negative value stop the must anticoagulation and will repeat the D-dimer test 15±2 days 
later. 
Pregnancy  is  highly  discouraged  in  these  patients  and  if  programmed  patients  are  
excluded  from  the  study.  If  sexually  active,  be  practicing  an  effective  method  of  birth  

 
 
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control  (e.g.,  intrauterine  device,  double-­‐barrier  method)  before  entry  and  throughout  
the  study. A pregnancy test is mandatory before enrollment. 
2. Course of the study: Every three-six months, a physical examination or a phone call will be 
made to assess compliance to treatment, health status and the occurrence of events.  
 
The follow up will be performed until the completion of the study for these kinds of patients: 
• 
those with persistently negative D-dimer who stopped anticoagulation,  
• 
those with positive D-dimer who continued or resumed anticoagulant treatment by assuming 
apixaban 2.5 mg BID, and  
• 
those with positive D-dimer who may refuse to assume apixaban as well as any other 
anticoagulant or antithrombotic agent for secondary VTE prevention, will be followed up for 
at least 18 months after recruitment in the study.  
• 
those who had premature discontinuation. 
 
 
Procedure 
Screeni
ng Visit 
(T0)  
D-Dimer test T1, T2, T3 
Last Visit 
Notes 
 
 
 
Patient 
with 
negative 
D-Dimer  
Patient 
with 
positive D-
Dimer 
Patient 
with 
positive  
D-Dimer 
who 
refuse 
Apixaban 
 
 
Eligibility Assessments 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
X 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
Safety Assessments 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
X 
 
Targeted Physical 
Examination 
X 
 
 
 
X 
 
Vital Signs 
X 
 
 
 
 
 
Assessment of Signs and 
Symptoms 
X 
 
 
 
X 
 
Compression Ultrasound 
Doppler (CUS) evaluation 
X 
 
 
 
 
 
Echocardiography 
evaluation 
X 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
D-Dimer Test 
X 
X 
 
 
 
 
Follow up every 3-6 
Months until 18 months 
 
X 
X 
X 
 
 
Clinical Drug Supplies 
 
 
 
 
 
 
Dispense Study Treatment  
 
 
X 
 
 
From the first 

 
 
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Procedure 
Screeni
ng Visit 
(T0)  
D-Dimer test T1, T2, T3 
Last Visit 
Notes 
 
 
 
Patient 
with 
negative 
D-Dimer  
Patient 
with 
positive D-
Dimer 
Patient 
with 
positive  
D-Dimer 
who 
refuse 
Apixaban 
 
 
positive D-Dimer 
test Apixaban will 
be dispensed every 
6 months 
Efficacy End Points 
 
 
 
 
 
 
Primary 
 
X 
X 
X 
X 
 
Secondary 
 
X 
X 
X 
X 
 
Safety End Points 
 
 
 
 
 
 
Primary 
 
X 
X 
X 
X 
 
Secondary 
 
X 
X 
X 
X 
 
 
 

 
 
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STATISTICAL CONSIDERATIONS 
 
The aim of this management study is to demonstrate that in patients with a first unprovoked VTE a 
combination of a prediction rule based on D-dimer and low-dose DOAC in those at higher recurrence 
risk result in a recurrence risk comparable to the population of patients with provoked VTE.  
 
Assumptions 
based on the results of the DULCIS study10, approximately 45% of all eligible patients are expected to 
discontinue anticoagulation, with an annual rate of recurrent VTE events around 3% (95% 2.0 to 
4.4%).  
In the remaining 55% of patients who will be encouraged to use apixaban, based on the results of 
the Amplify Extension study the expected rate of recurrent VTE is around 1.7% after the first year of 
treatment.  
Based on the metanalysis12 the annual recurrence risk in patients with provoked VTE is 3.3%  
 
Based on these assumptions, we expect the recurrence rate at 12 months to be:  
 
0.45*0.03+0.55*0.017=2.2% 
 
Sample size: With an expected annual recurrence rate of 2.2% in the APIDULCIS population, we 
calculated the sample size to demonstrate, with an 80% power, that the 95% CI is below 3.5% 
according to Shen 12. The required sample size is 1148 patients to be recruited for the purpose of the 
APIDULCIS study. 
 
Kaplan–Meier survival curves will be plotted to estimate the cumulative incidence of symptomatic 
recurrent VTE; hazard ratios (HR) and their 95% confidence intervals (CI) will be calculated for 
subgroup analyses. 
 
Safety end-points and interim analysis 
 
Based on a 2.2% annual event rate, a total sample size around 1150 patients and 18 months of 
follow-up, we expect around 38 recurrences and 2 major bleeding in our study. Since low-dose 
apixaban may be considered as the treatment gold-standard at the time of release of the study 
protocol, we plan an interim analysis when 20 primary endpoints are registered. The study will be 
interrupted if the relative risk of primary endpoints (HR) in the observational non-treatment arm will 
be >3 HR, with a p value <0.0001.  
 
 

 
 
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PROTOCOL SYNOPSIS 
 
Title: 
APIDULCIS: Extended anticoagulation with low-dose 
apixaban after a standard course anticoagulation in 
patients with a first venous thromboembolism who have 
positive D-dimer 
Country: 
Italy 
Number of Sites: 
53 centers 
Research Hypothesis: 
The cumulative incidence of VTE recurrence 10 years after 
stopping anticoagulation is about 50% and 20% after a first 
unprovoked  and  provoked event respectively.  It is not 
related to the duration of anticoagulant treatment. In 
addition, the rate of  fatal bleeding  on indefinite 
treatment is comparable to that of fatal PE in patients with  
anticoagulation discontinuation, and the case-fatality rate 
of major bleeding  is higher than that of symptomatic 
recurrent events 
The latest ACCP international guidelines suggest an 
indefinite duration of anticoagulation in all patients after 
an unprovoked event, at low or moderate risk of bleeding. 
All the available evaluations derive from studies on vitamin 
K antagonists (VKA) treatment.  The use of the novel direct 
oral anticoagulants (DOACs) offers a valid alternative to 
vitamin k antagonist and in particular, for the extended 
treatment, low-dose apixaban (2.5 mg BID) proved 
effective with better safety results than VKA. 
The DULCIS management study showed  that in VKA 
patients with an unprovoked (or associated with a weak 
risk factor) symptomatic episode of proximal DVT, serial D-
dimer measurement with the assessment of residual 
thrombosis allows to detect  those VTE patients at low 
recurrence risk (annual rate, 3.0%)  who can discontinue 
anticoagulation. 
The latest ACCP guidelines suggest the use  of D-dimer 
assessment after stop anticoagulation to decide the 
extended treatment. 
Study Schema: 
Drugs / Doses / 
Length of Treatment) 
Apixaban 2.5mg 
Treatment: 18 months 

 
 
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Study Objectives: 
Primary: 
Secondary: 
Primary  
Efficacy end-point: VTE recurrent  and VTE-related death  
Safety end-point: major bleeding   
 
Secondary: 
other thromboembolic events (severe) post-thrombotic 
syndrome (Villalta score) clinically relevant non major 
bleeding overall mortality 
Study Design: 
Phase IV, multicenter, national, prospective cohort study 
Accrual Goal: 
(Total number of subjects) 
1,200 
Accrual Rate: 
(Number of subjects 
expected per month)    
Recruitment time: 14-18 months 
Inclusion Criteria: 
Event that was unprovoked or associated with a risk factor 
that was removed  
Events that occurred in association with one or more risk 
factors that are no longer present 
Female and male patients of all ethnicity 
Signature of informed consent 
Age older than 18 or younger than 75 years 
Patients who completed 12-18 months of anticoagulation 
(whatever the drug used) 
 

 
 
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Exclusion Criteria: 
A)Exclusion criteria regarding the index event 
1)Events usually associated with low risk of recurrence 
 
DVT/PE occurred within 3 months from major surgery or 
major trauma 
Isolated Distal DVT (thrombosis of calf veins)  
 
2) Events associated with a very high risk of recurrence or 
occurrence of life-threatening recurrent events 
 
PE episode with shock or life-threatening 
Isolated PE with a systolic pulmonary artery pressure > 60 
mmHg at presentation 
DVT/PE associated with active cancer, antiphospholipid 
syndrome or long-standing medical illnesses 
More than one idiopathic event 
 
3) Index VTE events in different sites than deep veins of 
the lower limbs or pulmonary arteries 
  
B) Exclusion criteria present at the moment of patients’ 
screening: 
 
More documented unprovoked VTE episodes  
Pregnancy or puerperium or planning to become pregnant 
during the following 18 months  
Severe post-thrombotic syndrome (=> 15 points at the 
Villalta score) 
Solid neoplasia or blood disease in active phase or 
requiring chemotherapy/radiotherapy 
All the clinical conditions requiring prolonged treatment 
with LMWH   
Presence of overt, active chronic diseases (i.e. 
inflammatory bowel disease) 
Known serious thrombophilic alterations 
Any absolute contraindication to anticoagulant therapy 
Any contraindication to apixaban (as per local SmPC) 
Presence of antiphospolipid syndrome 
Presence of cava filter  
Concomitant conditions (such as atrial fibrillation) 
requiring indefinite anticoagulation  
Severe cardio-respiratory insufficiency (NYHA 3 or 4) 
Life expectancy shorter than 1 year 
Refuse interruption of anticoagulation to perform serial D-
dimer assessment 
Duration of anticoagulant treatment over 18 months 
Geographically inaccessible location  
Inability or refusal to give consent  
Patients already enrolled to other non observational 
clinical trials 

 
 
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Criteria for Evaluation: 
(Efficacy, safety, 
stopping rules, etc.) 
Criteria for definitions of efficacy and safety endpoints are 
detailed in Appendix 2; criteria for stopping rules are 
detailed in the interim analysis. 
Statistics: 
 
 
 
 
 
The aim of this management study is to demonstrate that 
in patients with a first VTE a combination of a prediction 
rule based on D-dimer and low-dose DOAC in those at 
higher recurrence risk result in a recurrence risk 
comparable to the population of patients with provoked 
VTE.  
 
Based on assumption, we expect the recurrence rate at 12 
months to be:  
 
0.45*0.03+0.55*0.017=2.2% 
Based on the aim of the study, that the rate of recurrence 
should be comparable, a rate estimate with sufficient 
precision is only necessary and there is no need to conduct 
hypothesis testing. The upper limit of the 95% CI can be 
below 0.035 for around 800 subjects given observed 
p=0.022.  
 
 
 
Kaplan–Meier survival curves will be plotted to estimate 
the cumulative incidence of symptomatic recurrent VTE; 
hazard ratios (HR) and their 95% confidence intervals (CI) 
will be calculated for subgroup analyses. 
 
Safety end-points and interim analysis 
 
Based on a 2.2% annual event rate, a total sample size 
around 1150 patients and 18 months of follow-up, we 
expect around 38 recurrences and 2 major bleeding in our 
study. Since low-dose apixaban may be considered as the 
treatment gold-standard at the time of release of the 
study protocol, we plan an interim analysis when 20 
primary endpoints are registered. The study will be 
interrupted if the relative risk of primary endpoints  (HR) in 
the observational non-treatment arm will be >3 HR, with a 
p value <0.0001.  
 
 
Study Drug/Treatment: Apixaban 
 
Study drugs: Apixaban 2.5 mg  

 
 
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The drugs will be provided by BMS.  
The investigated drug is Apixaban 2.5 mg, a film coated tablet. It should be administered orally, 
every day BID.  
The treatment should be performed for all the treatment period.  Drug product is to be stored 
according to labeled storage conditions. 
 
Patients who continue or resume anticoagulation will receive Apixaban 2.5 mg BID for 18 months 

 
 
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SAFETY AND REPORTING 
 
1. 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 an SAE.  
- 
Although pregnancy, overdose, potential drug-induced liver injury (DILI), and cancer are not 
always serious by regulatory definition, these events must be handled as SAEs. 
- 
Any component of a study endpoint that is considered related to study therapy should be 
reported as an SAE (eg, death is an endpoint, if death occurred due to anaphylaxis, 
anaphylaxis must be reported). 
NOTE: (PI determines if this information regarding hospitalizations are considered SAEs and 
should be included in the protocol. This is supplemental information that is included in 
BMS-sponsored trials) 
- 
The following hospitalizations are not considered SAEs in BMS clinical studies:  
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. 

 
 
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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). 
o Admission for administration of anticancer therapy in the absence of any other SAEs 
(applies to oncology protocols) 
 
ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a 
preexisting medical condition in a clinical investigation participant administered study drug and that 
does not necessarily have a causal relationship with this treatment. An AE can therefore be any 
unfavorable and unintended sign (such as an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of investigational product, whether or not considered related to 
the investigational product. 
The causal relationship to study drug is determined by a physician and should be used to assess all 
adverse events (AE). The casual relationship can be one of the following: 
Related: There is a reasonable causal relationship between study drug administration and the AE. 
Not related: There is not a reasonable causal relationship between study drug administration and 
the AE.  
The term "reasonable causal relationship" means there is evidence to suggest a causal relationship.  
Adverse events can be spontaneously reported or elicited during open-ended questioning, 
examination, or evaluation of a subject. (In order to prevent reporting bias, subjects should not be 
questioned regarding the specific occurrence of one or more AEs.) 
 
NONSERIOUS ADVERSE EVENT 
- 
Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim or final 
study reports as specified in the agreement or, if a regulatory requirement [eg, IND US trial] 
as part of an annual reporting requirement.  
- 
Non-serious AE information should also be collected from the start of a placebo lead-in 
period or other observational period intended to establish a baseline status for the subjects.  
A non-serious adverse event is an AE not classified as serious.  
 
Laboratory Test Abnormalities 
All laboratory test results captured as part of the study should be recorded following institutional 
procedures. Test results that constitute SAEs should be documented and reported to BMS as such. 
The following laboratory abnormalities should be documented and reported appropriately: 
- 
any laboratory test result that is clinically significant or meets the definition of an SAE 
- 
any laboratory abnormality that required the participant to have study drug discontinued or 
interrupted 
- 
any laboratory abnormality that required the subject to receive specific corrective therapy.  
It is expected that wherever possible, the clinical rather than laboratory term would be used 
by the reporting investigator (eg, anemia versus low hemoglobin value). 
 

 
 
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Adverse Events of Special Interest 
In this study, the following adverse events are to be reported to BMS, regardless of whether these 
reports are classified as serious or unexpected. 
 
 
Potential or suspected cases of liver injury including but not limited to liver test 
abnormalities, jaundice, hepatitis or cholestasis. 
 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study 
participant is pregnant or may have been pregnant at the time of investigational product exposure, 
including during at least 5 half-lives after product administration, the investigational product will be 
permanently discontinued in an appropriate manner (eg, dose tapering if necessary for participant).  
The investigator must immediately notify Worldwide.Safety@bms.com of this event via the 
Pregnancy Surveillance Form in accordance with SAE reporting procedures.  
Protocol-required procedures for study discontinuation and follow-up must be performed on the 
participant. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal 
outcome and, where applicable, offspring information must be reported on the Pregnancy 
Surveillance Form [provided upon request from BMS] 
Any pregnancy that occurs in a female partner of a male study participant should be reported to 
BMS. Information on this pregnancy will be collected on the Pregnancy Surveillance Form. In order 
for Sponsor or designee to collect any pregnancy surveillance information from the female partner, 
the female partner must sign an informed consent form for disclosure of this information.  
 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose of a product that is 
considered both excessive and medically important. All occurrences of overdose must be reported as 
an SAE. 
 
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.  
 
2. 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. All SAEs must be collected that occur during the screening period and within 

 
 
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30 days of discontinuing dosing. If applicable, SAEs must be collected that relate to any later 
protocol-specific procedure (such as follow-up skin biopsy). 
The investigator should report any SAE occurring after these time periods that is believed to be 
related to study drug or protocol-specified procedure.  
An SAE report should be completed for any event where doubt exists regarding its status of 
seriousness.  
If the investigator believes that an SAE is not related to study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy, or a complication of a study 
procedure), the relationship should be specified in the narrative section of the SAE Report Form. 
SAEs, whether related or unrelated to the study drug, and pregnancies must be reported to BMS 
within 24 hours. SAEs must be recorded on the CIOMS Form I Pregnancies on a Pregnancy 
Surveillance Form. 
SAE Email Address: Worldwide.Safety@BMS.com 
SAE Fax Number: 609-818-3804 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE 
reports should include the same investigator term(s) initially reported.)  
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 BMS (or designee) 
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 provided to BMS via annual safety reports (if applicable), and interim 
or final study reports. 
 
SAE Reconciliation 
The investigator will reconcile the clinical database SAE cases transmitted to BMS Global 
Pharmacovigilance (GPV&E). Reconciliation will occur every three months and once just prior to 
database lock/Final Study Report (FSR).  The investigator will request a safety data reconciliation 
report to AEPBUSINESSPROCESS@BMS.COM.  BMS GPV&E will e-mail upon request from the 
investigator, the GPV&E reconciliation report. The data elements listed on the GPV&E safety data 
reconciliation report will be used for case identification purposes. If the investigator determines a 
case was not transmitted to BMS GPV&E, the case will be sent immediately. 
 
 Note: Although not always adverse events by regulatory definition, the following events 
associated with a BMS product must be reported: 
 
- 
Exposure to infant during lactation 
- 
Lack of efficacy 

 
 
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- 
Abuse 
- 
Misuse 
- 
Off-label use 
- 
Occupational exposure 
- 
Medication error and potential medication error 
- 
Suspected transmission of an infectious agent e.g., any organism, virus or infectious 
particle pathogenic or nonpathogenic, via the medicinal product 
 
DATA COLLECTION DIRECTLY IN ELECTRONIC CASE REPORT FORM 
All sites participating in this study will use e-CRF for all data. 
The investigator is warned of any errors detected and can take action immediately. In addition, 
monitors and data manager(s) can follow the quality of 
the data input in real time and perform check of forms on line. Each modification is made by clicking 
on the item, which generates a change that the investigator validates electronically. 
 
CERTIFICATION OF THE DATA 
The data signature can follow immediately after the data input, or after an email request for 
validation is sent to the center investigator. A formatted version of the data can be submitted to the 
center investigator for control and validation at any time. 
 
SECURITY 
Each individual with access to the eCRF will have a user name and a password associated with a 
profile that defines user access level (access denied, read-only access, read-write capability) on each 
function of the application. For example, center investigators have full access to their patients data, 
not those of the other centers but they can consult them. 
STUDY TIMELINES 
• 
Estimated study period for recruitment: 14-18 months 
• 
Study period per patient: maximum duration 18 months 
• 
Estimated total duration of the study: 36 months 
• 
Scheduled first inclusion: September  2017 
• 
Report: 2021           
 
 
 
STUDY FEASIBILITY   
We expect that at each participating site at least 15 patients/18 months, in average 30/18 months 
will be enrolled. Thus, with the participation of 35-40 Italian centers we plan to complete enrolment 
in 18 months. With the last patient in completing the study follow-up in 18 months, study 
completion is expected in 3 years.    
 

 
 
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DATA QUALITY CONTROL 
 The trial will be monitored by the promoter according to the current Standard Operating Procedure 
for the monitoring of clinical trials. Shortly before the trial starts, the Trial Center Manager will meet 
with the investigator and all staff involved to review the procedures regarding trial conduct and 
recording the data into the eCRF system. During the trial, the investigator shall permit the Trial 
Center Manager to verify the progress of the trial at the center as frequently as necessary. The 
investigator shall make the electronic data screens available, provide missing or corrected data, and 
will correct the data in the eCRF system. Personal information will be treated as strictly confidential 
and will not be made publicly available. The promoter will ensure that appropriate Quality Control 
(QC) steps are included into the different clinical processes to guarantee adequate protection of the 
trial subjects and quality of the data. For any data transfer, measures will be undertaken to protect 
subject data handed over against disclosure to unauthorized third parties and subject confidentiality 
will be maintained at all times. 
  
ETHICAL CONDUCT OF THE STUDY 
The study will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and in compliance with national legislation.  The study will be conducted 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. Study personnel involved in this study will be qualified by education, training, and experience 
to perform their respective task(s).   
 
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 legislative decree 30th June 2003, n. 196.   
 
INFORMED CONSENT FORM 
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 

 
 
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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. Participation in this study is entirely voluntary.   
 
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.    
 
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 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   
Upon 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”.   
 

 
 
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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".  
 
 
Study Promoter  
Name: Fondazione Arianna Anticoagulazione 
Address: Via Paolo Fabbri 1/3 Bologna (BO) 
Phone 051 341471 
Fax 051 343604 
e-mail: fondazionearianna@anticoagulazione.it 
 
 
Coordinator Site 
SOD Malattie Aterotrombotiche AOU Careggi Firenze 
Principal Investigator 
Name : Daniela Poli 
Address: Viale Morgagni 85 Firenze 
Phone: 055-794545 
Fax  055-7946218 
e-mail  polida@aou-careggi.toscana.it   
 
 
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).         
 
 
 
 
 
 
 
 

 
 
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REFERENCES 
1. 
Prandoni P, Noventa F, Ghirarduzzi A, et al. The risk of recurrent venous thromboembolism 
after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or 
pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica the 
Hematology Journal 2007; 92: 199-205. 
2. 
Boutitie F, Pinede L, Schulman S, et al. Influence of preceding length of anticoagulant 
treatment and initial presentation of venous thromboembolism on risk of recurrence after 
stopping treatment: analysis of individual participants' data from seven trials. BMJ 2011; 342: 
d3036. 
3. 
Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline 
and Expert Panel Report. Chest 2016; 149: 315-52. 
4. 
Douketis JD, Gu CS, Schulman S, et al. The risk for fatal pulmonary embolism after 
discontinuing anticoagulant therapy for venous thromboembolism. Ann Intern Med 2007; 147: 
766-U36. 
5. 
Castellucci LA, Cameron C, Le Gal G, et al. Clinical and safety outcomes associated with 
treatment of acute venous thromboembolism: a systematic review and meta-analysis. JAMA 
2014; 312: 1122-35. 
6. 
Ageno W, Samperiz A, Caballero R, et al. Duration of anticoagulation after venous 
thromboembolism in real world clinical practice. Thromb Res 2015; 135: 666-72. 
7. 
Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous 
thromboembolism. N Engl J Med 2013; 368: 699-708. 
8. 
Simes J, Becattini C, Agnelli G, et al. Aspirin for the prevention of recurrent venous 
thromboembolism: the INSPIRE collaboration. Circulation 2014; 130: 1062-71. 
9. 
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. 
10. 
Palareti G, Cosmi B, Legnani C, et al. D-dimer to guide the duration of anticoagulation in 
patients with venous thromboembolism: a management study. Blood 2014; 124: 196-203. 
11. 
Cosmi B, Legnani C, Tosetto A, et al. Usefulness of repeated D-dimer testing after stopping 
anticoagulation for a first episode of unprovoked venous thromboembolism: the PROLONG II 
prospective study. Blood 2010; 115: 481-8. 
12. 
Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first episode of symptomatic 
venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern 
Med 2010; 170: 1710-6. 
13. 
Shen LZ. Sample size determination for controlling the upper confidence limit of incidence rate 
of a binomial endpoint. J Biopharm Stat 1998; 8: 489-96. 
14. 
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. 
15. 
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. 
 

 
 
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APIDULCIS STUDY 
APPENDIX 1 
TIMING OF D-DIMER MEASUREMENTS  
D-dimer should be measured at the following time points after anticoagulation is 
stopped. 
 
T0 
= during anticoagulation 
T1    = 15±2 days after anticoagulation is stopped 
T2  
= 30±4 days after anticoagulation is stopped  
T3  
= 60±5 days after anticoagulation is stopped 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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PREDEFINED CUT-OFF LEVELS FOR NEGATIVE/POSITIVE 
 
D-dimer cut-off levels (ng/ml) for males and females (aged 18-75 years) 
 
 
 
Males 
Females 
Methods with results in FEU 
 
- 
VIDAS D-Dimer (bioMerieux) 
- 
Innovance D-dimer (Siemens) 
- 
Sta Liatest D-Di (Diagnostica Stago) 
- 
HemosIL D-Ddimer HS 500 (Werfen) 
- 
HemosIL D-Dimer HS (Werfen) 
- 
AcuStar D-Dimer (Werfen) 
 
 
350 ng/mL 
0.35 mg/L 
0.35 µg/mL 
350 ng/mL 
350 ng/mL 
350 ng/mL 
 
 
500 ng/mL 
0.50 mg/L 
0.50 µg/mL 
500 ng/mL 
500 ng/mL 
500 ng/mL 
Methods with values in DDU 
- 
HemosIL D-Dimer HS (Werfen) 
- 
HemosIL D-Dimer (Werfen) 
- 
Sclavo Auto D-dimer (Dasit) 
 
175 ng/mL 
175 ng/mL 
175 ng/mL 
 
250 ng/mL 
250 ng/mL 
250 ng/mL 

 
 
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APPENDIX 2 
 
OUTCOME DEFINITIONS 
 
VENOUS THROMBOEMBOLISM (VTE) 
 
Pulmonary embolism (PE) 
 
Symptoms of PE with one of the following findings. 
 A new intraluminal filling defect in (sub) segmental or more-proximal branches on 
spiral computed tomography (CT) of the chest. 
 A new intraluminal filling defect, or an extension of an existing defect, or a new 
sudden cutoff of vessels more than 2.5 mm in diameter on the pulmonary angiogram. 
 A new perfusion defect of at least 75% of a segment, with a local normal ventilation 
result (high probability) on ventilation/perfusion lung scintigraphy (VQ scan). 
 Inconclusive spiral CT, pulmonary angiography, or VQ scan evidence of a new or 
recurrent PE, with demonstration of a new or recurrent deep vein thrombosis (DVT) 
in the lower extremities by compression ultrasound (CUS) or venography. 
 
 
Proximal deep vein thrombosis (DVT) 
 
Symptoms of DVT with one of the following findings. 
 
(a) For a NEW DVT: abnormal CUS, or an intraluminal filling defect on venography. 
 
(b) For a RECURRENT DVT: 
 abnormal CUS where compression had been normal or, if non-compressible during 
screening, a substantial increase (4 mm or more) in diameter of the thrombus during 
full compression, or 
 an extension of an intraluminal filling defect, or a new intraluminal filling defect, or an 
extension of non-visualization of veins in the presence of a sudden cut-off on 
venography. 
 
 
DEATH 
 
For all patients who died during the study, the cause of death was adjudicated to one of the 
following categories. 
 
 VTE-related death 
 PE (based on objective diagnostic testing, autopsy) 
 Unexplained death (and VTE cannot be ruled out) 
 Sudden death (and VTE cannot be ruled out). 

 
 
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 Cardiovascular (CV)-related death 
 Myocardial infarction (MI) 
 
Stroke 
 
 Other CV event (to be specified). 
 
 Other 
 Cancer 
 Bleeding 
 Infectious disease 
 Other known cause (to be specified). 
 
 
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. 

 
 
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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. 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Flow-chart of the study