Which Decision After a First Venous Thromboembolism? The WHITE Study
Conditions: Venous Thromboembolism
Sponsor: Arianna Anticoagulazione Foundation

WHITE Study Protocol – Final Version – 20 September 2017 
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Version and date: final version – 20 September 2017 
 
Study code: WHITE Study 
 
 
Study Title: WHITE Study: WHIch decision after a first venous ThromboEmbolism? 
[Multicenter, multinational, investigators-initiated, observational, prospective study to evaluate the 
decisions taken by clinicians at the end of the maintenance treatment of subjects with a first-ever event of 
deep vein thrombosis of the lower limbs and/or pulmonary embolism, the relevant reasons, and the 
attending long-term outcomes] 
 
Study Promoter: Fondazione Arianna Anticoagulazione, Bologna (Italy) 
 
International study coordinator: Jiří Matuška 
 

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1. Table of contents 
1. Table of contents ........................................................................................................................................................ 2 
2. List of abbreviations ................................................................................................................................................... 4 
3. Responsible parties .................................................................................................................................................... 5 
3.1 Individual responsible parties .............................................................................................................................. 5 
4. Synopsis ...................................................................................................................................................................... 7 
5. Amendments ............................................................................................................................................................ 11 
6. Rationale and justification ........................................................................................................................................ 11 
6.1 Background ........................................................................................................................................................ 11 
6.2 Justification of the study .................................................................................................................................... 11 
7. Research question and objectives ............................................................................................................................ 12 
7.1 Research question .............................................................................................................................................. 12 
7.2 Objectives ........................................................................................................................................................... 12 
7.2.1 Primary objective ..................................................................................................................................... 12 
7.2.2 Secondary objectives ............................................................................................................................... 12 
8. Methods ................................................................................................................................................................... 13 
8.1 Study design ....................................................................................................................................................... 13 
8.1.1 Primary endpoint ..................................................................................................................................... 13 
8.1.2 Secondary endpoints ................................................................................................................................ 13 
8.1.3 Considerations on the study design ......................................................................................................... 13 
8.2 Study set-up ....................................................................................................................................................... 14 
8.2.1 Eligibility ................................................................................................................................................... 14 
8.2.2 Inclusion criteria ....................................................................................................................................... 14 
8.2.3 Exclusion criteria ...................................................................................................................................... 14 
8.2.4 Withdrawal from study ............................................................................................................................ 14 
8.2.5 Replacement ............................................................................................................................................ 15 
8.3 Study procedures ............................................................................................................................................... 15 
8.3.1 Visits ......................................................................................................................................................... 15 
8.3.2 Variables ................................................................................................................................................... 17 
8.3.3 Source of data .......................................................................................................................................... 17 
8.4 Data management .............................................................................................................................................. 18 
8.5 Quality assurance ............................................................................................................................................... 18 
9. Protection of the subject’s rights ............................................................................................................................. 18 
9.1 Study conduct .................................................................................................................................................... 18 
9.2 Ethics Committee/Institutional Review Board ................................................................................................... 18 
9.3 Informed consent ............................................................................................................................................... 19 
9.4 Subjects insurance ............................................................................................................................................. 19 
9.5 Confidentiality .................................................................................................................................................... 19 
10. Statistics .................................................................................................................................................................. 19 
10.1 Statistical considerations ................................................................................................................................. 19 
10.2 Sample size ....................................................................................................................................................... 19 
10.3 Populations ...................................................................................................................................................... 21 
10.4 Data analysis .................................................................................................................................................... 21 
10.4.1 Demographic, prognostic and descriptive variables .............................................................................. 21 
10.4.2 Primary endpoint ................................................................................................................................... 21 
10.4.3 Secondary endpoints .............................................................................................................................. 21 
10.4.4 Other endpoints ..................................................................................................................................... 22 
10.4.5 Safety observations ................................................................................................................................ 22 

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11. Committees ............................................................................................................................................................ 22 
11.1 Steering Committee ......................................................................................................................................... 22 
11.2 Writing Committee........................................................................................................................................... 23 
11.3 Data Monitoring and Safety Board .................................................................................................................. 23 
12. Plans for disseminating and communicating study results .................................................................................... 24 
13. References .............................................................................................................................................................. 25 
Appendices ................................................................................................................................................................... 26 
Appendix I – Information sheet ............................................................................................................................... 26 
Appendix II – Documentation of informed consent ................................................................................................. 29 
Appendix III – Declaration of new recruitment according to protocol .................................................................... 30 
Appendix IV – CRF template ..................................................................................................................................... 31 
 

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2. List of abbreviations 
 
DMSB 
Data Monitoring and Safety Board 
DVT 
Deep Venous Thrombosis 
EC 
Ethics Committee 
e-CRF 
Electronic Case Report Form 
IRB 
Institutional Review Board 
LMWH 
low-molecular-weight heparin 
NOAC 
New Oral Anti-Coagulant 
PE 
Pulmonary Embolism 
VKA 
Vitamin K Antagonist 
VTE 
Venous Thrombo-Embolism 
 

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3. Responsible parties 
3.1 Individual responsible parties 
Function: 
Promoter 
Name: 
Gualtiero Palareti 
Institution: President, Fondazione Arianna Anticoagulazione 
Address: 
info@fondazionearianna.org 
 
Function: 
International Study Coordinator 
Name: 
Jiří Matuška 
Institution: Clinical Trial Centre, Hodonin, Czech Republic 
Address: 
jiri.matuska@matmed.cz 
 
Function: 
Study Statistician 
Name: 
Angelo A. Bignamini 
Institution: University of Milan, Italy 
Address: 
angelo.bignamini@unimi.it 
 
Function: 
National Study Coordinator, Russia 
Name: 
Victor Barinov 
Institution: Department of Surgery of Central State Medical Academy of the President Administration 
of Russian Federation , Clinical hospital N. 1"Volynskaya", Moscow, Russia 
Address: 
vicbarin@mail.ru 
 
Function: 
National Study Coordinator, Tunisia 
Name: 
Kamel Bouslama 
Institution: Faculty of Medicine of Tunis, Tunisia 
Address: 
kamel.bouslama387@gmail.com 
 
Function: 
National Study Coordinator, Romania 
Name: 
Maria Dorobantu 
Institution: "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania 
Address: 
maria.dorobantu@gmail.com 
 
Function: 
National Study Coordinator, China 
Name: 
Young-Jun Li 
Institution: Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China 
Address: 
liyongjun4679@bjhmoh.cn 
 
Function: 
National Study Coordinator, Slovakia 
Name: 
Juraj Madaric 
Institution: National Institute of Heart and Vascular Diseases, Bratislava, Slovakia 
Address: 
madaricjuraj@gmail.com 
 

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Function: 
National Study Coordinator, Portugal 
Name: 
Armando Mansilha 
Institution: University of Porto, Portugal 
Address: 
vascular.mansilha@gmail.com 
 
Function: 
National Study Coordinator, Czech Republic 
Name: 
Jiří Matuška 
Institution: Clinical Trial Centre, Hodonin, Czech Republic 
Address: 
jiri.matuska@matmed.cz 
 
Function: 
National Study Coordinator, Mexico 
Name: 
Carlos Ruben Ramos Lopez 
Institution: Mexican Council of Angiology, Vascular & Endovascular Surgery, Guadalajara, Mexico 
Address: 
rramos@megared.net.mx 
 
Function: 
National Study Coordinator, Poland 
Name: 
Tomasz Urbanek 
Institution: Medical University of Silesia, Katowice, Poland 
Address: 
urbanek.tom@interia.pl 
 
Function: 
Core Team Member 
Name: 
Jiří Matuška 
Institution: Clinical Trial Centre, Hodonin, Czech Republic 
Address: 
jiri.matuska@matmed.cz 
 
Function: 
Core Team Member 
Name: 
German Y. Sokurenko 
Institution: North-West Mechnikov State Medical University, St.Petersburg, Russia 
Address: 
german_sokurenko@mail.ru 
 
Function: 
Core Team Member and 
DMSB Member 
Name: 
Gualtiero Palareti 
Institution: University of Bologna, Italy 
Address: 
gualtiero.palareti@unibo.it 
 
Function: 
Core Team Member and 
DMSB Member 
Name: 
Giuseppe M. Andreozzi 
Institution: Past Director Angiology Unit, University of Padua, Italy 
Address: 
gm.andreozzi@gmail.com 
 
 
 
Function: 
Core Team Member and 
DMSB Member 
Name: 
Angelo A. Bignamini 
Institution: University of Milan, Italy 
Address: 
angelo@aabignamini.it 

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4. Synopsis 
Title of the study 
WHITE Study: WHIch decision after a first venous ThromboEmbolism? 
[Multicenter, multinational, investigators-initiated, observational, prospective 
study to evaluate the decisions taken by clinicians at the end of the 
maintenance treatment of subjects with a first-ever event of deep vein 
thrombosis of the lower limbs and/or pulmonary embolism, the relevant 
reasons, and the attending long-term outcomes] 
Code of the study  
WHITE Study 
Version 
Final Version 
Date 
20 September 2017 
Design of the study 
international, non-profit, multicenter, observational, prospective 
Promoter of the study 
Fondazione Arianna Anticoagulazione, Bologna (Italy) 
International Coordinator 
of the study 
Jiří Matuška 
Rationale 
Patients having experienced a first-ever episode of DVT of the lower limbs and/or PE, 
receive anticoagulation therapy for a period as recommended by international and/or 
local practice guidelines. When this recommended period expires, the attending 
physician has to decide whether to continue with anticoagulation, switch to anti-
thrombotic of another class, or stop any prophylactic pharmacological treatment. Little 
is known as to which proportion of subjects is assigned to each alternative, whether this 
proportion is equivalent across different countries, different healthcare systems, and 
very little is known about the reasons guiding the physician’s decision. 
After the decision is taken, a number of validated data is available in the literature 
regarding the outcomes in subjects assigned to extended anticoagulation for up to one 
year, whereas little if any information is available for subjects receiving extended 
anticoagulation for more than one year, or assigned to alternative long-term treatment, 
or who stopped the treatment. 
The Fondazione Arianna promotes this international, investigators-initiated, 
multicenter observational study, to collect data that may possibly answer the first 
question, and give substantial indications concerning the second question. 
Main objective of the 
study 
This study includes two sections: 
a] a transversal section, in which the primary objective will be evaluated; 
b] a longitudinal section, in which the secondary objectives will be evaluated. 
It is assumed that the distribution of the decision taken during the transversal section 
(primary objective) may influence the outcomes of the longitudinal section. 
The primary objective of the study is the evaluation of the distribution of decisions and 
of the reasons guiding the physician’s decision on the modality to manage the 
secondary prevention of venous thromboembolism (VTE) in patients treated for a first-
ever episode of VTE, after the initial 3-12 months of anticoagulation therapy. 
The secondary objective is the collection of data on the course of VTE recurrence, 
bleeding and death risk. 
Endpoints of the study 
Primary endpoint:  
The primary endpoint is the decision taken by the attending physician at the end of the 
period of maintenance anticoagulation (from the end of the 3rd month to the end 12th 
month) initiated after the index event (maintenance anticoagulation). The maintenance 
anticoagulant used may or may not be the same used in the acute phase of DVT (initial 
7 days); for the objectives of this study, the acute treatment is not of interest. The 
primary endpoint will be evaluated at the visit performed at the end of the 
maintenance anticoagulation. 
 
Secondary endpoints 
The distribution of reasons guiding the physician’s decision on the modality to manage 
the secondary prevention of VTE represents a secondary endpoint. 
The other secondary endpoints encompass the frequency of thromboembolic 
complications, of bleeding complications, or death from any cause monitored during 
the follow-up. 

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Number of Countries 
Nine: Portugal, Poland, Czech Republic, Slovakia, Rumania, Russia, Tunisia, China, 
Mexico 
Number of Centers  
Approximately from 5 to 20 Centers in each Country. Each center shall recruit not more 
than 40 subjects. 
Number of patients 
A minimum number of 3,200 subjects will be enrolled across all the countries 
participating to the study, split into: 
approximately 200 subjects in China  
approximately 350 subjects in Czechia;  
approximately 300 subjects in Mexico;  
approximately 900 subjects in Poland;  
approximately 350 subjects in Portugal;  
approximately 250 subjects in Romania;  
approximately 800 subjects in Russia;  
approximately 150 subjects in Slovakia;  
not less than 100 subjects in Tunisia. 
Period of enrolment 
Not more than eighteen months 
Period of follow-up 
Two years 
Inclusion criteria 
a) subjects who provided a written informed consent and authorization for disclosure 
of protected health information; 
b) male and female adult or elderly patients (18 years at the time of signing the 
informed consent; no upper limit) of any ethnicity having had a first-ever event of 
provoked or unprovoked DVT of the lower limbs and/or PE given maintenance 
anticoagulants (NOACs, VKAs, or LMWHs) according to the local procedures (usually 
for 3 to 12 months) and to be re-evaluated to decide the treatment to be prescribed 
after such period; 
c) for whom the center is in possession of all the data relevant to the index event; 
d) having a permanent reference contact. 
Exclusion criteria 
a) subjects <18 years old; 
b) subjects unable or unwilling to issue the written informed consent; 
c) subjects for whom the information relevant to the index event are incomplete or 
inaccessible to the Investigator; 
d) subject in whom the index event was a DVT not of the lower limbs; 
e) subjects with life expectancy of less than 2 years; 
f) subjects participating in any other clinical study, regardless of its nature; 
g) subjects considered, by the attending physician, unable to comply with the study 
procedures. 
Study Procedures 
Enrollment and baseline visit: 
1. the physician will assess the inclusion/exclusion criteria for entering the study and 
obtain the informed consent to confer the study data; 
2. after obtaining the consent, the attending physician will record the diagnostic and 
prognostic information required in the CRF and inform the promoter of the 
recruitment of the patient; 
3. the attending physician, based exclusively on the personal judgment and in 
accordance with the local procedures, will decide whether to continue with 
anticoagulation (NOACs or VKAs or LMWHs); or to switch to a long-term 
antithrombotic prophylaxis; or permanently discontinue the pharmacological 
prophylaxis. This decision generates three sub-populations with regards to the 
secondary prophylaxis of VTE: 
a] subjects receiving extended anticoagulation, with the same or another 
substance of the same class, at the same or lower dose as used in the 
maintenance treatment; 
b] subjects receiving long-term antithrombotic non-anticoagulant prophylaxis; 
c] subjects not receiving any long-term pharmacological prophylaxis. 
4. the attending physician will record in the CRF the reasons guiding the decision 
taken; 
5. the physician will instruct the subject on the procedures of the follow-up that 
should be the normal procedures in use at the Center, will provide a contact 

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reference and will obtain a contact reference. 
 
Follow-up visits 
The follow-up will be articulated as normally performed at the Center. The common 
follow-up procedures include a telephone contact every 3/6 months (4/8 in two years) 
and a direct interview at the center at least once a year (two in two years). 
At each follow-up contact, by telephone or personal, information will be collected on: 
a. survival at the time of contact; 
b. hospitalizations occurred after the previous contact; 
c. events of thromboembolic complication; 
d. events of bleeding complication: 
e. changes in the antithrombotic/anticoagulant therapy, if any was prescribed, 
including the institution of an antithrombotic/anticoagulant therapy if none had 
been prescribed; 
f. other events that prevent the continuation of the planned follow-up. 
 
Unplanned follow-up visits 
It is possible, as usual during long-term monitoring of subjects, that visits are needed at 
the center upon request by the subject or based on the physician’s decision. These 
unplanned visits, which will typically correspond to an event of recurrence or of 
bleeding, will record the same information as a standard follow-up visit. Performing an 
unplanned visit is not by itself considered a reason for terminating the study, unless the 
visit corresponds to one of the study endpoints (thromboembolic complications, 
bleeding complications, or other events preventing continuation of the follow-up). 
 
End-of-study visit 
The end-of-study information, collected at the last planned or unplanned contact with 
the subject, will only include the reason for terminating the observation on the 
individual subject. 
The end-of-study visit will have to be completed for all subjects entered into the follow-
up, and may occur: 
a) at the end of the planned follow-up period; 
b) when the investigator detects, or is informed of, the occurrence of a secondary 
endpoint (new thromboembolic event, major bleeding, clinically relevant non-major 
bleeding requiring a change of treatment; subject’s death); 
c) change (with the exception of dosage) or interruption of the prophylactic treatment 
assigned at recruitment (including not pharmacological treatment) by the attending 
physician or other physician; 
d) subject’s decision to stop the prescribed prophylaxis; 
e) events occurred, which prevented the continuation of the follow-up (subjects lost 
to follow-up for any reason, including reporting to another center). 
Sample size justification 
The primary endpoint is the decision taken by the attending physician at the end of the 
maintenance anticoagulation initiated after the index event. Three options are possible 
and in absence of other determinants, the null hypothesis is that the distribution of 
subjects by option is uniform. The analysis can therefore be performed with a 
goodness-of-fit test with 2 degrees of freedom. The alternative hypothesis is that at 
least one of the three choices is selected in a greater proportion than the other two. 
This analysis is performed once only at the end of recruitment. 
With approximately 3,200 subjects, the study has 90% power to detect with 95% 
confidence a deviation from the uniform distribution, in case one of the options is 
selected in a proportion exceeding by 10% relative or more the proportion expected 
from the uniform distribution (i.e., in 36.3% or more of the subjects). 
The study also has 80% power to detect with a two-tailed 97% confidence (accounting 
for interim analyses) a deviation of at least one of the sub-populations, by at least: 
a] ±1.23 recurrence events from the expected rate of 5 events per 100 subjects per 
year, and 
b] ±0.55 bleeding events/deaths from the expected rate of 1 event per 100 subjects 
per year. 
Statistical-analytical plan 
Statistical considerations 
The statistical analyses will be descriptive and exploratory. Given the nature of the 

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study, which is observational, it is not designed to confirm or reject predetermined 
hypotheses. 
 
Populations 
The analyses will be performed on the total sample monitored. Missing data will not be 
replaced. 
 
Demographic, prognostic and descriptive variables 
All variables will be summarized with the usual descriptive techniques: categorical 
variables as contingency table (absolute and relative frequency); continuous variables 
with sampling statistics: mean, standard deviation, median, minimum, maximum. 
Whenever appropriate the relevant 95% confidence interval will also be reported. 
 
Primary endpoint 
The primary endpoint will be analyzed at the completion of the recruitment. The 
proportion of choices made by the attending physician will be reported as proportion 
with confidence interval by level. The primary analysis will test by goodness-of-fit 
whether the choices were random or not. The impact of demographic and prognostic 
factors – including country – on the choice can be tested by chi square and/or logistic 
regression analysis. 
 
Secondary endpoints 
Frequency of thromboembolic complications and frequency of bleeding complications 
or death for any reason will be analyzed at the completion of each year of observation. 
The interim results will be used by the DMSB to decide on whether the observation has 
to continue or must be stopped. The final analysis will be adjusted for multiplicity using 
the nominal critical P value of 0.03. 
Event rates will be reported at the available observations, stratified by sub-population, 
as proportion with the relevant confidence interval. Proportions will be compared if 
appropriate by chi square and/or as time to event by survival analysis. 
Since clinically-relevant non-major bleeding may not be a reason for interrupting the 
follow-up, and minor bleeding are not a reason for interruption, it is possible that the 
number of bleeding events per subject can be submitted to analysis by Poisson 
regression. 
The other secondary endpoint is the reason(s) justifying the choice analyzed as primary 
endpoint. These will be tabulated by choice and compared, if appropriate, by chi square 
test or by ordinal logistic regression. Unplanned post-hoc subgroup analyses may be 
performed if requested by the Steering Committee. 
 
Other endpoints 
Occurrence of hospitalization and changes of prophylactic therapy, including institution 
of a therapy in subjects who stopped any prophylactic treatment at recruitment; 
change of the prophylactic treatment assigned at recruitment, and interruption of the 
prophylactic treatment assigned at recruitment. 
Hospitalizations will be analyzed as proportion of subjects with event, compared 
between sub-populations, if appropriate, by chi square or in case of an appreciable 
number of events, by Poisson regression. 
Changes in therapy will be tabulated as absolute number and proportion stratified by 
sub-population and, if appropriate, analyzed by chi square and/or logistic regression. 
In addition, the reasons for study termination may be considered an endpoint. These 
will be tabulated by sub-population and compared, if appropriate, by chi square or 
ordinal logistic regression. 
 
Safety observations 
Adverse events will be handled by the attending physician according to the local 
procedures and, as in any observational study, will not be subject to statistical analysis. 
Only those events that resulted in the interruption of follow-up will be tabulated by 
sub-population and/or individual medication, without further statistical considerations. 
 

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5. Amendments 
This is the final protocol version subject to the approval by the relevant Ethics Committees (EC)/Institutional 
Review Boards (IRB). Subsequently, possible amendments will be submitted to the relevant EC/IRB before 
being implemented and will constitute a separate document. In case of major amendments, a new 
comprehensive version of the protocol may be prepared, incorporating all the minor and major amendments 
approved until that date. 
6. Rationale and justification 
6.1 Background 
The reference international guidelines [1] recommend initial treatment of DVT of the lower limbs and/or 
PE with a direct anticoagulant (oral or parenteral) followed by a period of anticoagulation therapy with 
the same direct oral anticoagulant or partially overlapping it with a Vitamin K antagonist (VKA), with a 
preference for the former alternative. 
An exception is represented by a VTE associated with an active cancer. In this case, a treatment with 
parenteral anticoagulant (in particular LMWH) for the whole period of 3 months is recommended. 
Anticoagulation therapy is essential for at least three months in all cases. The incidence of VTE recurrence is 
considered to be very low when an event is triggered by surgery or another specific risk factor. In these 
cases, a three-month treatment is considered sufficient. In case of idiopathic (unprovoked) events, however, 
such period may not be sufficient due to the marked tendency of VTE to recur. In these cases, it is advisable 
to assess each subject's specific benefit (expected decrease in recurrences) in comparison with the risk of 
bleeding associated with prolonged anticoagulation, and determine the duration of anticoagulation based on 
this evaluation. However, pre-determined time-limited courses of therapy longer than 12 months are 
unusual [1]. In addition, based on the local healthcare system, not all regimens can be protracted indefinitely 
in all cases. 
At the end of the three months – or longer, usually not more than one year – of anticoagulation, the 
attending physician has to decide whether and how to manage the long-term secondary prevention of 
recurrences, based on an assessment of the individual ratio of risks of recurrence and of bleeding. These 
individual estimates are often difficult to evaluate. A number of additional factors also influence the decision, 
including subject’s predicaments and preferences, concurrent diseases and treatments, healthcare system 
support, and availability of potentially effective alternative treatments, such as aspirin [2] and sulodexide [3]. 
The choice of whether to continue at all the secondary prophylaxis and, if continued, the selection of the 
appropriate treatment and the relevant duration after maintenance anticoagulation, is therefore far from 
standardized. The practical clinical behavior may consequently be very dissimilar case to case, and practice 
guidelines, literature and local healthcare provisions do not help much in facing this problem. 
6.2 Justification of the study 
At the end of the recommended or practicable period of anticoagulation after a first-ever episode of VTE, the 
attending physician has therefore three different options:  
1. 
continue with extended anticoagulation using a treatment of the same or other anticoagulant class 
(NOACs or VKAs or LMWHs) at the same dosage as in the previous period or with a lower dosage; 
2. 
replace the anticoagulant with an alternative antithrombotic (including antithrombotic proper, 
antiplatelet or vasoprotective drug) with or without compression therapy;  
3. 
interrupt any specific pharmacological treatment (with or without compression therapy).  

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Little is known as to which proportion of subjects is assigned to each alternative and whether this proportion 
is equivalent across different healthcare systems, and very little is known about the reasons guiding the 
physician’s decision. 
After the decision is taken, a number of validated data is available in the literature regarding the outcomes in 
subjects assigned to extended anticoagulation for up to one year, [4-6] whereas little if any information is 
available for subjects receiving extended anticoagulation for more than one year, or assigned to alternative 
long-term treatment, or who stopped the treatment. 
The Fondazione Arianna promotes this international, investigators-initiated, multicenter observational study, 
to collect data that may possibly answer the first question, and give substantial indications concerning the 
second question. 
7. Research question and objectives 
7.1 Research question 
The research question prompting this study is the decisional process that assigns subjects with previous VTE 
who concluded the maintenance anticoagulation, to one of the alternative options: extended 
anticoagulation, alternative pharmacological prophylaxis, or interruption of the pharmacological prophylaxis. 
The secondary research question is the estimation of the true rate of events during prolonged observation 
under true-to-life conditions, among subjects allocated to extended anticoagulation or to alternative 
prophylaxis or to no pharmacological prophylaxis. 
7.2 Objectives 
7.2.1 Primary objective 
The primary objective of the study is the assessment of the distribution of decisions on the modality to 
manage the secondary prevention of venous thromboembolism (VTE), at the end of the period of 
anticoagulation considered standard. This period, initiated after the index event and defined in the present 
protocol as maintenance anticoagulation, ranges from the end of the 3rd month to the end 12th month. The 
anticoagulant used for the maintenance anticoagulation may or may not be the same used in the initial acute 
phase of VTE management (the initial 7 days). To the effect of this study, the treatment applied during the 
acute phase is of no interest. 
7.2.2 Secondary objectives 
The distribution of the reasons guiding the physician’s decision indicated in § 7.2.1 is to be considered a 
secondary objective since, to date, there is no indication as to whether and which factor may represent an 
explanatory variable guiding the decision taken. 
The secondary objective is the collection of data on the course of thromboembolic complications, bleeding 
complications and death risk, during a relatively prolonged follow-up. This information is already available in 
the literature for subjects who continued with anticoagulation for up to one year [4-6], whereas no solid 
information is available for subjects under longer treatment or who switched to an alternative 
antithrombotic prophylaxis or interrupted the treatment. 
The period of follow-up after terminating the standard anticoagulation treatment is limited in this study to 2 
years, since there is no evidence that after such period the risk of events is different from that of a matched 
population without a previous VTE episode. Since data on late recurrence rates are contrasting and 
somewhat obsolete, a DMSB is established to guide the conduct of the study (§ 11.3). 

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8. Methods 
8.1 Study design 
This is an international, no-profit, multicenter, observational, prospective study. The study encompasses two 
sections: 
a] a transversal section, in which the primary objective (and the related secondary objective on the reasons 
suggesting the primary objective) will be evaluated; 
b] a longitudinal section, in which the other secondary objectives will be evaluated. 
The transversal section includes one population; the decision representing the primary endpoint, taken 
during the initial visit, will instead generate three sub-populations with regards to the secondary prophylaxis 
of VTE: 
a] 
subjects receiving extended anticoagulation, with the same or another substance of the same class, at 
the same or lower dose as used in the maintenance treatment; 
b] 
subjects receiving long-term antithrombotic non-anticoagulant prophylaxis; 
c] 
subjects not receiving any long-term pharmacological prophylaxis. 
The secondary endpoints collected during the follow-up will be stratified by sub-population. 
8.1.1 Primary endpoint 
The primary endpoint is the proportion of subjects allocated by the attending physicians at the end of 
the maintenance anticoagulation initiated after the index event, by free and spontaneous decision, to 
one of the three possible options: 
a) 
continue with anticoagulation, using the same substance or a substance of the same class, with the 
same or lower dosage (“extended anticoagulation”), with or without compression therapy; 
b) 
replace the anticoagulation with an alternative treatment (with or without compression therapy),  
c) 
interrupt any pharmacological prophylactic treatment (with or without compression therapy). 
The primary endpoint will be evaluated at the first visit, that is, at the end of the maintenance 
anticoagulation. 
8.1.2 Secondary endpoints 
The secondary endpoints include: 
• the distribution of the reasons that were considered relevant by the attending physician to take the 
decision indicated as primary endpoint; 
• the rate of thromboembolic complications and the combined rate of bleeding requiring at least an 
interview with the attending physician (major or clinically relevant non-major bleeding), or death from 
any cause during the 2-year follow-up. 
8.1.3 Considerations on the study design 
This is an observational study. As such, it allows collecting information based on the usual clinical 
practice as performed in the day-to-day clinical care of the target subjects. 
However, as any investigator-initiated observational study, it may have a bias associated with the propensity 
of the individual investigator to participate in non-sponsored studies, with the local availability of personnel 
and time to collect and enter data, and with the investigator’s willingness and capability to ensure an 
appropriate quality assurance on the collected data. 

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As in any clinical trial, furthermore, the need to obtain the written informed consent to data collection may 
also introduce a bias, which will probably select the more educated segment of the potential participants 
and, in any case, is likely to affect the consecutiveness of recruited cases. 
8.2 Study set-up 
8.2.1 Eligibility 
Approximately 3,200 subjects will be enrolled. Each center will recruit not more than 40 among the 
consecutive subjects coming to the observation after approval of the protocol by the relevant EC/IRB until 
the total planned number of cases is overall collected. Consecutiveness may be replaced by other mean of 
bias containment if necessary given the center operational structure (e.g., all consecutive subjects reporting 
each first week of the month, a definite day in the week, or similar provisions). The selected predefined 
modality of screening and including patients should be declared by the participant centers. The subjects shall 
be able and willing to issue the informed consent to confer their data. Male and female adult and elderly 
subjects of any ethnicity, having had a first-ever event of DVT of the lower limbs and/or PE, treated with 
anticoagulants according to the local procedures but for not less than 3 and not more than 12 months, and 
having reached the final decision point on the therapy, are eligible to enter the study. 
8.2.2 Inclusion criteria 
Subjects meeting all of the following criteria qualify for entry into the study: 
a) 
subjects who provided a written informed consent and authorization for disclosure of protected health 
information; 
b) 
male and female adult or elderly subjects (18 years at the time of signing the informed consent; no 
upper limit); 
c) 
of any ethnicity; 
d) 
with a first-ever event of provoked or unprovoked DVT of the lower limbs and/or PE treated with 
anticoagulants (NOACs, VKAs, or LMWHs) according to the local procedures (usually for 3 to 12 months) 
and to be re-evaluated to decide the treatment to be prescribed after this period; 
e) 
for whom the center possesses all the data relevant to the index event; 
f) 
having a permanent reference contact. 
8.2.3 Exclusion criteria 
Subjects meeting any of the following criteria will not qualify for entry into the study: 
a) 
subjects <18 years old at the time of consent request; 
b) 
subjects unable or unwilling to issue the written informed consent; 
c) 
subjects for whom the information relevant to the index event are incomplete or inaccessible to the 
Investigator; 
d) 
subject in whom the index event was a DVT not of the lower limbs; 
e) 
subjects with life expectancy of less than 2 years; 
f) 
subjects participating in any other clinical study, regardless of its nature; 
g) 
subjects considered, by the attending physician, unable to comply with the study procedures.  
8.2.4 Withdrawal from study 
Each subject has the right to refuse to continue on study at any moment and without justifications. 
However, since the study data are the usual data that the investigator collects for the standard subject’s 
care, “withdrawal” should be intended as retiring the consent to the collection of subject’s data into the 
study database. Consequently, from the moment a subject withdraws from the study, subsequent 

WHITE Study Protocol – Final Version – 20 September 2017 
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information should not be collected among the study data. On the contrary, unless specifically indicated 
by the subject, all data collected up to that point will be retained among the study data. 
8.2.5 Replacement 
As usual in observational studies, no replacement is planned for subjects who retire the consent to 
confer the study data. 
8.3 Study procedures  
Being this an observational study, all the procedures, therapeutic decisions and clinical assessments will 
be performed according to the standard, country specific clinical practice for the management of this 
kind of subjects. 
8.3.1 Visits 
The study does not anticipate other visits than those normally planned in the diagnostic-therapeutic course 
of the considered subjects. The visits are those of the normal routine. The period of observation for each 
subject is that normally anticipated by the clinical practice. The informed consent to the collection of data 
will equally be obtained during the course of a routine visit. 
1. Enrollment and baseline visit 
The enrollment and baseline visit is the normally planned visit in which the physician has to decide on the 
continuation of the secondary prophylaxis after a first-ever thromboembolic episode treated for an 
appropriate period with anticoagulants. Due to organizational reasons, the enrollment and baseline visit may 
occur after the conclusion of anticoagulation. The time interval between conclusion of anticoagulation and 
enrollment visit should not exceed one month. 
At the enrollment visit, all candidate subjects will receive an information sheet explaining design and aims of 
the study. The clinician shall explain and ask the subject to sign the informed consent form to confer the 
study data. The consent will also include the subject’s agreement to receive regular phone calls from the 
investigator during the follow-up and to report annually to the center. The consent form will be part of the 
center documents and the only information conferred to the database will be whether the consent was 
signed or not, and in which date. The investigator will be responsible to archive the signed form for possible 
verification. 
Subsequently, the investigator will: 
• 
verify the inclusion/exclusion criteria for entering the study; 
• 
inform by fax/mail the study Promoter that a new subject has been enrolled according to the protocol 
(form in Appendix III); 
• 
obtain the information on the index event; 
• 
monitor the clinical condition of veins and record the Villalta score; 
• 
record the vascular risk factor, the concurrent diseases and the medications on long-term use; 
• 
record the minimum clinical information required (weight, height, blood creatinine) as available; for 
creatinine, the last known serum creatinine level not older than three months before entering the study 
is appropriate; 
• 
record the maintenance anticoagulation treatment received; 
• 
decide on the subsequent subject’s management and record the decision; the decision should be taken 
in the exclusive subject’s interest and based exclusively on the personal judgment and in accordance 
with the local procedures; 
• 
record the new form of management, if any; 
• 
record the reasons influencing the decision taken; 

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• 
instruct the subject on the procedures of the follow-up, which should be the normal procedures in use 
at the center; 
• 
provide a contact reference and obtain a contact reference. 
2. Follow-up visit 
The normal procedures for the long-term follow-up of these subjects include a number of calls – in 
general every 3 to 6 months – and a yearly recall at the center for a personal interview. The anticipated 
number of follow-up contacts is of approximately 4 to 8 calls and 2 interviews at the center, over the 2-
year observation. 
The information collected at calls and interviews are the usual ones used to monitor the status of the 
subject, and include: 
a. 
survival status; 
b. 
hospitalizations; 
c. 
thromboembolic complications; 
d. 
bleeding complications; 
e. 
review of the prophylactic treatment, if any was prescribed, and relevant changes if deemed 
necessary; 
f. 
other events that prevent the continuation of the planned follow-up. 
3. Unplanned follow-up visit 
Upon request of the subject, or by decision of the investigator based on the communications with the 
subject, there may be the need for unplanned follow-up interviews. This will usually occur when a 
thromboembolic complication or a bleeding complication or other events occurred, that make clinically 
relevant for the well-being of the subject a direct contact with the investigator. 
The information to be collected at these visits is the same as that of the follow-up visit. Usually, these 
visits imply the conclusion of the follow-up on the individual subject. 
The follow-up is to be concluded, filling the end-of-study form discussed below, when: 
a. 
a thromboembolic complication occurred; 
b. 
a major bleeding complication occurred. Clinically relevant non-major bleedings as well as minor 
bleedings do not automatically imply the interruption of the follow-up and the relevant decision will 
be taken by the investigator case by case on the best subject’s interest; 
c. 
there was a substantial change in anti-thrombotic therapy, such as: 
• 
institution, by the investigator or another physician, of a prophylactic therapy in a subject for 
whom the decision was taken not to continue the pharmacological prophylaxis; 
• 
replacement, by the investigator or another physician, of the current therapy with a new 
therapy of another therapeutic class. Changes of dosage of the same therapy do not imply 
interruption of the follow-up; 
• 
interruption, by the investigator or another physician or by subject’s spontaneous decision, of 
the prescribed prophylactic treatment; 
d. 
an event occurred, that implied the impossibility to continue a correct monitoring, e.g., a 
planned/unplanned intervention requiring prolonged anticoagulation (e.g., surgery or 
immobilization). 

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4. End-of-study visit 
Each subject will have an end-of-study visit. This does not represent an independent visit, but a simple 
recording of the end of monitoring for the individual subject, and will coincide with: 
a. 
the last contact, usually at the center, at the end of the 2-year observation; 
b. 
the planned or unplanned follow-up visit at which any of the events terminating the follow-up have 
occurred, as indicated in the unplanned follow-up visit (thrombotic complication, major bleeding 
complication, substantial change in therapy, other event preventing continuation of the follow-up); 
c. 
the investigator is informed that the subject died; 
d. 
the subject ceased reporting to the center and started reporting to another hospital; 
e. 
the subject moved the residence to a place preventing continuation of the follow-up; 
f. 
the subject was lost to follow-up without additional information. 
8.3.2 Variables 
The variables to be collected in this study are the usual descriptive, diagnostic and prognostic variables 
normally recorded in the subject’s cards, as well as the description of the antithrombotic treatments applied 
and the reason for change. In the follow-up, the usual outcome variables relevant to the subject’s status will 
also be collected. 
a. descriptive variables 
These include age, sex, ethnicity. 
b. diagnostic variables 
These include complete description of the index event, including the putative cause of a secondary event and 
risk factors for the event. 
c. prognostic variables 
These include body weight, height and creatinine (to estimate BMI and creatinine clearance); clinical 
conditions of veins with calculation of the Villalta score; active concurrent diseases, vascular risk factors, 
medications in long-term use. 
d. treatment information 
This includes type, dosage and duration of the maintenance anticoagulation performed; type, dosage and 
planned duration of the new treatment proposed, if any, and the classification of the reasons considered by 
the investigator for the decision taken. 
e. outcome variables during the follow-up 
These include type and time of contact, classification of the events (thrombotic complications, bleeding 
complications, survival, hospitalization) occurred in the period since the last contact, and information on the 
current therapy, if any, and relevant changes regardless of whether decided by the investigator, another 
physician, or spontaneously by the subject. 
8.3.3 Source of data 
The source of data is the information collected into, or to be recorded into, the subject’s hospital card or 
equivalent documents. No additional data are requested. 

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8.4 Data management 
The investigators will directly manage the primary data, as usual. The responsibility to properly collect and 
record the data into the hospital, center or other subject’s documents remains with the individual attending 
physicians. The responsibility to collect, verify and record possible adverse drug reactions remains with the 
local responsible for pharmacovigilance. 
The investigator and/or specifically appointed co-investigator(s) will transfer the study data to the study 
database. The study data will be entered into an e-CRF, accessible from a standard personal computer with 
the use of standard browsers. The database will be unique and centralized, to facilitate maintaining proper 
database security with the usual maintenance procedures (data encryption, backups, checks of consistency 
and integrity, etc.). All data to be transferred will by anonymized; only the investigator and co-investigators 
will locally retain a log in which the correspondence between the study unique code and the subject’s 
identification will be possible. This log will not exit the hospital, but shall be kept available for possible 
verifications within the frame of the quality assurance procedures (§ 8.5). 
Each investigator and duly delegated co-investigator will have a personal username and password allowing 
access to the centralized database. All investigators at one Center can have access to the data of their center. 
In this context, “center” means an operating unit in which one or more investigators monitor a number of 
subjects, who are not seen for the same reason by other units. 
8.5 Quality assurance 
This is an investigators-initiated study; therefore, each investigator assumes the responsibility to guarantee 
the quality of the data recorded in the subject’s documents. The National coordinator, in accordance with 
the local investigator, may require to inspect and verify the core data, in particular the subjects’ log and the 
informed consent forms. The local database operators assume the responsibility to guarantee the quality of 
the data conferred to the central database in accordance with the procedures setup in the database manual. 
The statistical responsible of the study will verify completeness, accuracy and plausibility of the data 
recorded onto the database, producing if needed requests for additional verification against the raw data 
recorded in the subjects’ documents. Only after the final verification after the study closure, the database 
will be frozen and submitted to statistical analysis. 
9. Protection of the subject’s rights 
The study will be performed in compliance with the Declaration of Helsinki 
(http://www.wma.net/en/30publications/10policies/b3/) and the applicable sections of the Good Clinical 
Practice, as well as in compliance with the international and national regulations. 
9.1 Study conduct 
This is an observational study in which the medications prescribed, if any, are prescribed by the attending 
physician according to the relevant Authorization to Commercialization, in the best subject’s interest, based 
on the training and expertise of each physician. No diagnostic or therapeutic action is anticipated by this 
protocol, which are not normally planned for the appropriate monitoring and follow-up of the subjects. 
9.2 Ethics Committee/Institutional Review Board 
Each center participating in this study should obtain the authorization to participate by the relevant EC/IRB. 
Copy of this authorization shall be sent to the promoter of the study and also kept by the investigator until 
the end of the study, and may be subject to verification by the National Coordinator. In case of protocol 
amendments, it is the Investigator’s responsibility to submit such amendments to the relevant EC/IRB, 
according to the Center’s procedures. 

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9.3 Informed consent 
Before conferring any data to the study database, the investigator shall obtain the consent from each 
subject, after having supplied adequate information. To be recruited, the subjects must have given the 
individual consent in writing to the management of personal data in anonymous and aggregate form. Each 
subject shall be informed that can withdraw the consent at any time of the study, without penalties and 
without justification (§ 8.2.4). The information sheet and the consent form to the use of personal data are 
appended to this protocol. The documentation of consent shall be archived by the local investigator until the 
end of the study, and may be subject to verification by the National coordinator. It is responsibility of the 
Investigator’s or a delegate to record onto the database that the consent was obtained, with the relevant 
date, and to inform the study promoter of the recruitment of a new subject according to the protocol. This 
information, however, is associated in the database to the subject’s unique study code, without personal 
identification data. 
9.4 Subjects insurance 
This study collects data on the routine management of subjects with drugs used in the indications 
authorized, at doses and in dosage forms duly authorized. The diagnostic, therapeutic and monitoring 
procedures of the study follow the routine planned for these subjects. The participants do not incur into any 
additional risk or discomfort because of their participation in the study. Consequently, no specific insurance 
is needed. 
9.5 Confidentiality 
All subjects managing the study data guarantee to maintain the confidentiality of the subjects’ personal data. 
In particular, the investigator and co-investigators, who have access to sensible data, guarantee to keep 
confidential any information they might become aware of, as in the normal clinical practice. The entire 
documentation available outside the center is instead anonymized and does not contain information that 
might allow identifying the participating subjects. 
10. Statistics 
10.1 Statistical considerations 
The statistical analyses will be descriptive and exploratory. Given the nature of the study, which is 
observational, it is not designed to confirm or reject predetermined hypotheses. The hypothesis indicated in 
the sample size calculation is to be considered supportive of the physicians’ attitude towards methods of 
long-term prophylaxis, to be eventually confirmed by specifically designed motivational investigations. 
10.2 Sample size 
The study anticipates recruiting approximately 3,200 subjects, based on considerations relevant to the 
primary endpoint. 
The primary endpoint is the decision taken by the attending physician at the end of the maintenance 
anticoagulation initiated after the index event. Three options are possible: continue with extended 
anticoagulation (regardless of individual drug and dose), replace the anticoagulation with an antithrombotic, 
non-anticoagulant treatment, or stop any pharmacological prophylactic treatment. 
In absence of other determinants, the null hypothesis is that the distribution of subjects by option is uniform. 
The analysis can therefore be performed with a goodness-of-fit test with 2 degrees of freedom. The 
alternative hypothesis is that at least one of the three choices is selected in a greater proportion than the 
other two. This analysis is performed once only at the end of recruitment. 

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With approximately 3,200 subjects, the study has 90% power to detect with 95% confidence a deviation from 
the uniform distribution, in case one of the options is selected in a proportion exceeding by 10% relative or 
more the proportion expected from the uniform distribution (i.e., in 36.3% or more of the subjects) [7]. 
Given that the factor “country” (synonymous of “healthcare system”) will be a likely cofactor in the analyses, 
the sample should be split across the participating countries in such a way the allow a reliable 
representativeness also for the smaller countries. The limit was considered not less than 100 subjects per 
country. The anticipated contribution by country was therefore estimated as: 
Country 
cases 
China 
approximately 200 
Czechia 
approximately 350 
Mexico 
approximately 300 
Poland 
approximately 900 
Portugal 
approximately 350 
Romania approximately 250 
Russia 
approximately 800 
Slovakia 
approximately 150 
Tunisia 
not less than 100 
 
Since in this study the secondary endpoints are of clinical relevance as well, it is appropriate to estimate 
whether the indicated sample can yield reliable information also in relation to such endpoints. 
The secondary endpoints are the rate of thromboembolic complications and the combined rate of bleeding 
complications/death. To allow the DMSB (§ 11.3) to take appropriate decisions on the conduct of the study, 
these analyses will be performed at yearly intervals, i.e., when the last recruited subject has reached the end-
of-year observation. There will therefore be 2 analyses (1 interim and one final), so that the final analysis will 
have to report as statistically relevant and deserving further investigations, P-values 0.048.[8] 
The interest of the study is to find whether any of the three constituted sub-populations – extended 
anticoagulation; long-term antithrombotic prophylaxis; no pharmacological prophylaxis (§ 8.1) – deviates 
from the expected risk, to an extent deserving investigation of the potential predictors of outcome. 
From the literature [2, 3], the estimated annual risk of recurrence in the control group was approximately 5 
events per 100 subject-years. The combined risk of bleeding or death was approximately 1 event per 100 
subject-years. 
Assuming that almost all recruited subjects will be monitored for at least one year, this survey has 80% 
power to detect with a two-tailed 95% confidence (after accounting for the interim analyses) a Cohen’s effect 
of the baseline decision taken on the follow-up outcomes, of 0.055 [9]. It can therefore identify as potentially 
relevant, deviations of at least one of the constituted sub-population from the anticipated recurrence rate of 
at least ±0.0123 (3.77 or less, or 6.23 or more, events per 100 patients per year). Similarly, it has 80% power 
to detect with a two-tailed 95% confidence a deviation of at least one of the three constituted sub-
populations from the anticipated bleeding/death rate of ±0.0055 (0.45 or less, or 1.55 or more, events per 
100 patients per year). [10] 

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10.3 Populations 
As usual in the observational studies, the analyses will be performed on the total sample monitored. Only 
subjects specifically indicated by the Steering Committee as major, irreconcilable deviation will be excluded 
from analysis (§ 11.1). Missing data will not be replaced. Subgroup analyses are not anticipated, however – 
given the exploratory nature of the study – unplanned subgroups analyses may be performed post-hoc, upon 
indications by the Steering Committee. 
10.4 Data analysis 
10.4.1 Demographic, prognostic and descriptive variables 
All variables will be summarized with the usual descriptive techniques: categorical variables as contingency 
table (absolute and relative frequency); continuous variables with sampling statistics: mean, standard 
deviation, median, minimum, maximum. Whenever appropriate the relevant 95% confidence interval will be 
reported. 
10.4.2 Primary endpoint 
The primary endpoint will be analyzed at the completion of recruitment. The proportion of choices made by 
the attending physician will be reported as proportion with confidence interval by level. The primary analysis 
will test by goodness-of-fit whether the choices were random or not. The impact of demographic and 
prognostic factors – including the country – on the choice may be tested, if appropriate, by chi square and/or 
logistic regression analysis. 
Unplanned post-hoc subgroup analyses may be performed if requested by the Steering Committee. 
10.4.3 Secondary endpoints 
The secondary endpoint analyzable at the completion of recruitment is the reason(s) justifying the choice 
analyzed in 10.4.2. These will be tabulated by choice and compared, if appropriate, by chi square test or by 
ordinal logistic regression. Unplanned post-hoc subgroup analyses may be performed if requested by the 
Steering Committee. 
The other secondary endpoints include the frequency of thromboembolic complications and the frequency of 
bleeding complications or death for any reason. These will be analyzed at the completion of each year of 
observation (full year of observation of the last subject entered into the long-term follow-up). The interim 
results will be used by the DMSB to decide on whether the observation has to continue or must be stopped. 
The final analysis will be adjusted for multiplicity using the nominal critical P value of 0.048. 
Event rates will be reported at the available observations as proportion, stratified by sub-population, with 
the relevant confidence interval. Deviations from the expected rate of events will be analyzed by chi square 
and/or time to event by survival analysis. If appropriate, subgroups will be analyzed with the Cox survival 
model. Impact of putative predictors as indicated by the Steering Committee will be analyzed by logistic 
regression and/or Cox proportional-risk model. 
Since clinically-relevant non-major bleeding may not be a reason for interrupting the follow-up, and minor 
bleedings are not a reason for interruption, it is possible that the number of bleeding events per subject can 
be submitted to analysis by Poisson regression. 

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10.4.4 Other endpoints 
Other monitored endpoints include the occurrence of hospitalization and the change of prophylactic therapy, 
including: 
• institution – by the attending physician or other physician - of a therapy in subjects who stopped any 
prophylactic treatment at recruitment; 
• change – by the attending physician or other physician - of the prophylactic treatment assigned at 
recruitment, and  
• interruption – by the attending physician, other physician or by spontaneous subject’s decision - of the 
prophylactic treatment assigned at recruitment. 
Hospitalizations do not necessarily imply interruption of the follow-up, unless associated to a primary 
endpoint (thromboembolic event, bleeding, death) or result in the impossibility to continue an appropriate 
monitoring (e.g. need for anticoagulation). Consequently, hospitalizations can be analyzed by chi square 
across sub-populations as proportion of subjects with event or, in case of an appreciable number of events, 
by Poisson regression. 
Any change in therapy, instead, implies interruption of the follow-up. Changes in therapy will be tabulated, 
stratified by sub-population, as absolute number and proportion and, if appropriate, analyzed by chi square 
and/or by logistic regression. 
In addition, the reasons for study termination may be considered an endpoint. These will be tabulated by 
sub-population and compared, if appropriate, by chi square or ordinal logistic regression. If required by the 
Steering Committee, unplanned post-hoc subgroup analyses may also be performed. 
10.4.5 Safety observations 
Being this an observational study in which any prescription is by free physician’s choice in accordance 
with the drug’s technical data sheet, all safety information will be handled by the attending physician 
according to the local procedures. Since, however, events may occur, which are not endpoints but may 
imply the termination of the follow-up, these events will be tabulated by sub-population and/or 
individual medication, without additional statistical considerations. 
11. Committees 
The Promoter will setup the Committees listed at continuation, to ensure the correct execution of the study 
and the respect of the subjects’ rights. 
11.1 Steering Committee 
The study will be guided and monitored by a Steering Committee. The members of the Steering Committee 
are listed in § 3.1 above. 
The Steering Committee has the responsibility of: 
a. supervising the progress of the study and ensuring that the protocol is carefully followed by every 
participant. To exert this responsibility the Steering Committee may appoint Monitors and, in such a case, 
is informed of all monitoring activities and, in particular, of the reports of the Data Monitoring and Safety 
Board (§ 3.2.3). 
b. proposing Protocol Amendments to solve, clarify and implement possible doubts, questions, or practical 
difficulties that may arise during the study, or that may become necessary owing to the scientific progress 
in the specific therapeutic field, to ensure that the scientific validity of the study is maintained. 

WHITE Study Protocol – Final Version – 20 September 2017 
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c. resolve doubts as to the classification of outcomes, if the need arises. To this aim, the individual subject’s 
data supplied to the Committee will be anonymous as to the subject and to the Center, and blinded as to 
the applied treatment, if any. 
d. resolve doubts as to the protocol violation, if any, deciding whether the possible violation is to be 
considered a minor deviation, a major deviation, or a true violation, and whether the case has to be 
included into the ITT dataset (no other dataset is planned in this study). To this aim, the individual 
subject’s data supplied to the Committee will be anonymous as to the subject and to the Center, and 
blinded as to the applied treatment. 
e. participate in the Writing Committee. 
The Steering Committee appointed a Core Team of five persons, including a statistician. The Core Team has 
the responsibility of: 
a. 
managing the study according to the needs that may arise, and reports to the whole Steering Committee 
as needed; 
b. 
presenting to the Steering Committee a yearly report on the status of the trial, including the clinical 
results that may arise, until the closure of the study, which will incorporate the conclusions of the DMSB 
evaluation. The term “yearly” should be intended as the time at which the data relevant to the end-of-
observation-year visit on the last subject recruited have been recorded and validated. Consequently, 
there will be one interim report; the second report coincides with the final study report. 
The components of the Core Team are listed in § 3.1 above. 
11.2 Writing Committee 
The Writing Committee is composed of the Steering Committee and additional investigators if needed, based 
primarily on number of subjects enrolled and secondarily by speed of recruitment. The Writing Committee is 
led by the Core Team. 
The Writing Committee has the responsibility of: 
a. 
preparing the main publication of the study results; 
b. 
deciding on additional and subsequent publications of planned and unplanned study results: 
c. 
requesting additional statistical analyses of the study data, in relation to the publications indicated 
above; 
d. 
defining the list of authors to each publication; 
e. 
managing the contacts with the Journals and the requests for clarification and modifications to the 
submitted papers. 
11.3 Data Monitoring and Safety Board 
The study shall be supervised by a specifically set-up DMSB. 
The main purpose of the DMSB is to protect subjects, primarily those included in the trial but also other 
subjects with the disease in question. The second responsibility of the DMSB is to ensure the integrity of the 
study, in particular in the form of compliance with the procedures indicated in the protocol to ensure the 
data credibility. 
The DMSB will be composed of three members including a statistician. The members of the DMSB should not 
be enrolling subjects into the study. 
The DMSB has also the responsibility to recommend to the Steering Committee changes in the conduct of 
the study, whenever changes of clinical practice or information gathered in the study or in other ongoing 
studies suggest that the current conduct might have negative effects on the subjects’ wellbeing. 

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The decision of the DMSB will be taken on data collected at the end of every year of long-term follow-up (i.e., 
when the last subject to be observed has completed the observation at the end of a full year). 
Since there will be a total of 2 analyses of the endpoints monitored during the follow-up (one interim and 
one final), to maintain the overall alpha error at 0.05, the final analysis of these endpoints will report as 
statistically significant at the 95% level of confidence, P-values ≤0.048. 
12. Plans for disseminating and communicating study results 
This study will be registered at “www.clinicaltrials.gov". Results will be disclosed in a publicly available 
database within the standard timelines. 
The results of this observational study are intended to be published in a peer-reviewed journal and as 
abstracts/presentations at medical congresses under the oversight of the Promoter. Current guidelines and 
recommendation on good publication practice will be followed (e.g. STROBE [8]). To retain the integrity of 
the multicenter study, no individual investigator may publish on the results of this study, or their own 
subjects, or their country’s subjects, without prior coordination with the Promoter. 

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Guideline and Expert Panel Report. Chest 2016; 149: 315-52. 
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Brighton TA, Eikelboom JW, Mann K, Mister R, Gallus A, Ockelford P, et al. Low-dose aspirin for 
preventing recurrent venous thromboembolism. N Engl J Med 2012; 367: 1979-87. 
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Andreozzi GM, Bignamini AA, Davi G, Palareti G, Matuska J, Holy M, 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. 
4. 
Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Porcari A, Raskob GE, Weitz JI; AMPLIFY-
EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 
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5. 
EINSTEIN Investigators, Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, 
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H, Cohen A, Davidson BL, Piovella F, Schellong S. Oral rivaroxaban for symptomatic venous 
thromboembolism. N Engl J Med 2010; 363: 2499-2510.  
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Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, 
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dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368: 709-18 
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Faul F, Erdfelder E, Lang A-G, Buchner A. G*Power 3: A flexible statistical power analysis program for the 
social, behavioral, and biomedical sciences. Behavior Research Methods 2007; 39: 175-191. 
8. 
Reboussin DM, DeMets DL, Kim K, Lan KKG. Programs for computing group sequential boundaries using 
the Lan-DeMets method. Department of Biostatistics, University of Wisconsin, Madison (USA), 1996. 
9. 
Cohen J. Statistical power analysis for the behavioral sciences (2nd ed.). 1988; Hillsdale (NJ), Lawrence 
Erlbaum. 
10. Champely S. pwr: Basic Functions for Power Analysis. 2016; R package version 1.2-0. http://CRAN.R-
project.org/package=pwr. 
11. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP; STROBE Initiative. The 
Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines 
for reporting observational studies. J Clin Epidemiol 2008; 61: 344-9. 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 26 of 45 
Appendices 
 
Appendix I – Information sheet 
Protocol Code: WHITE Study 
Final Version of 20 September 2017 
 
PATIENT’S INFORMATION SHEET 
Study: 
WHITE Study: WHIch decision after a first venous ThromboEmbolism? 
[Multicenter, multinational, investigators-initiated, observational, prospective study to 
evaluate the decisions taken by clinicians at the end of the maintenance treatment of 
subjects with a first-ever event of deep vein thrombosis of the lower limbs and/or pulmonary 
embolism, the relevant reasons, and the attending long-term outcomes] 
Center:  
 _________________________________________________________________  
Investigator:  _________________________________________________________________  
 
 
Dear Madam, dear Sir. 
You are being requested to participate in this study, promoted by a Foundation for Anticoagulation 
(Fondazione Arianna Anticoagulazione, Bologna, Italy) because you had a thrombosis that is being treated 
until now with anticoagulants. 
You have now reached the time in which we should decide your treatment for the future. The decision can be to 
continue with the same treatment, to use another treatment, or simply to stop the treatment. We will take this 
decision in this visit. 
To have a better understanding on how often and why one of these alternatives are taken, it is important that 
this decision is documented in a great number of persons and, possibly, that the results of the decision taken 
will have over the next years will also be recorded. 
We ask your authorization to make available, within the limits and in compliance with the current regulations, 
some of your clinical data, which are useful to complete a research that aims at making more clear which 
decision is taken, why, and what are the effects over the following years, up to two years from now. 
Your participation does not imply any additional action from your side: you will be treated and monitored, as 
you would be in any case. This is the meaning of an “observational” research. The only difference from the 
normal care and follow-up is that you allow the Promoter – the Fondazione Arianna – to use for research some 
of your data. These data will remain completely anonymous. 
The information you may provide, together with the information collected anonymously in more than 3,000 
other patients all over the world, can help designing a more effective and efficient management for future 
patients with your same problem. The results obtained from these data can also be the object of scientific 
communications, but in no instance it will be possible that you are identified through these data. 
 
1. OBJECTIVES OF THE STUDY 
The objectives of the study are the comprehension of how many patients are allocated to the different 
alternatives for the long-term management of a previous thrombosis, and why. In addition, there is also the 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 27 of 45 
objective to monitor over a relatively extended period of time the true risks of thrombosis and of bleeding, in 
specific subgroups of persons. 
 
2. WHAT PARTICIPATING TO THE STUDY IMPLIES 
The collaboration that is requested from you consists in the authorization to collect and manage some of your 
clinical and personal data, in a completely anonymous way, to perform the study. 
You will also be requested to permit us to call every three to six months to ask some information, and to plan 
an interview with us at this center every year, for the next two years. These calls and the yearly visit are in any 
case part of our normal plans for the long-term follow-up of persons like you. The only difference is that the 
data we ask or monitor will be recorded into the study data, always in a completely anonymous way. 
This “observational” study does not plan for any exam or treatment in addition to those that are normally 
planned by your doctor to monitor the course of your recovery. 
The participation to this study does not imply any additional cost, nor any saving, compared with your normal 
medical care. 
 
3. POTENTIAL BENEFITS FROM PARTICIPATING TO THE STUDY 
Participating to this study will not result in any direct and immediate clinical benefit for you or the other 
participants. The results of the study, however, can give important indication on how to manage on the long 
term the recovery of persons who had a thrombosis, that can improve or make more efficient the management 
of other persons in the future. 
 
4. POTENTIAL RISKS FROM PARTICIPATING TO THE STUDY 
There will be no risks due to the administration of drugs or treatments different from those normally 
prescribed to you by your Doctor.  
 
5. YOUR RIGHTS 
You are free to refuse participating in the study, or to retire your consent to the collection of your data, without 
forewarning or justification. In any case, you will continue receiving the best care appropriate for your medical 
condition. 
The investigator is responsible for correctly carrying out the clinical protocol within the norms and regulation 
of the good clinical practice and within the frame of this information sheet. The investigator is available for any 
reasonable request of explanation or clarification from your side for what concerns the collection of the study 
data. 
The results of this study will be retained as strictly confidential and anonymous. The results may be made 
known to others or published, but excluding any possible reference to you or to other participants. The local 
norms for the protection of personal data will strictly be adhered to. 
For the entire duration of your participation to the study, you may ask information and questions to the 
Investigator concerning the data collected in the study and the course of the study. Similarly, at the end of the 
study you may request that your data be communicated to you and/or to your family physician. 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 28 of 45 
6. PATIENT’S RESPONIBILITIES 
This study is “observational”. Consequently, you will have no direct responsibility on the conduct and 
execution of the study, except the responsibility to decide whether you want to take part or not in the proposed 
study, by signing the Informed Consent form. 
Should you refuse to participate, you will in any case receive the care for your clinical condition you are 
entitled to. 
 
7. FURTHER USEFUL INFORMATION 
This study is no profit; it is promoted by the non-profit Foundation Arianna Anticoagulazione of Bologna 
(Italy). 
The protocol of the study proposed to you was redacted in accordance with the current Good Clinical Practice, 
with the current Declaration of Helsinki, and was approved by the Ethics Committee/Institutional Review 
Board of this structure. 
 
8. USE AND PROTECTION OF DATA 
The collected information will be read, processed, analyzed and presented by the parties involved in the study 
and perhaps by the competent Authorities. Your data will be coded and your identity will not be revealed, nor 
will it be publicly available. This information will be handled as strictly confidential and in accordance with the 
applicable laws and regulations. This information will be used only for your most appropriate care and for the 
aims of the study. 
As already indicated, the results of this study may be made known to the Authorities, to others or published in 
scientific papers. The presentation of results will be coded, excluding any possible reference to you or to other 
participants. You will not be identified in any report or publication. The local norms for the protection of 
personal data will strictly be adhered to. 
 
The Doctor(s) involved in the collection of your data is/are: 
 
Dr.  .................................................................................................................  
Dr.  .....................................................................................................................  
telephone:  ..............................................................................................  
telephone:  ..................................................................................................  
e-mail:  .......................................................................................................  
e-mail: .............................................................................................................  
 
and are at your disposal for any further information relevant to the study you may want to have. We thank you 
very much for your attention and collaboration. 
 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 29 of 45 
Appendix II – Documentation of informed consent 
Protocol Code: WHITE Study 
Final Version of 20 September 2017 
 
INFORMED CONSENT FORM 
Study: 
WHITE Study: WHIch decision after a first venous ThromboEmbolism? 
[Multicenter, multinational, investigators-initiated, observational, prospective study to 
evaluate the decisions taken by clinicians at the end of the maintenance treatment of 
subjects with a first-ever event of deep vein thrombosis of the lower limbs and/or pulmonary 
embolism, the relevant reasons, and the attending long-term outcomes] 
Center:  
 _________________________________________________________________  
Investigator:  _________________________________________________________________  
 
Did you have sufficient time to read, understand and, if needed, receive additional explanations concerning what is 
written in the information sheet? 
YES 
NO 
Did you receive from the Doctor indicated above sufficient explanations concerning your participation to the 
observational study indicated above? 
YES 
NO 
Could you pose all the questions you deemed necessary, receiving satisfactory answers? 
YES 
NO 
Did you consult your family physician or other persons concerning this study? 
YES 
NO 
If you did not consult other persons, was it because you considered such request not necessary? 
YES 
NO 
Have you been informed of your right to withdraw from the study at any time, without explanations and without 
affecting you medical care? 
YES 
NO 
Are you aware that you may ask at any time information on the course of the study for what you are concerned? 
YES 
NO 
Did you receive the name and telephone number of the Doctor you may contact at any time to receive further 
information relevant to the study? 
YES 
NO 
Do you authorize the persons responsible for the conduct of this observational study to handle your data and to 
have periodical contacts with you to obtain additional data? 
YES 
NO 
Do you authorize the persons responsible for the study and other competent authorities to have access to your 
study data, which will in any case be treated as strictly confidential? 
YES 
NO 
Did you receive a copy of the Information Sheet and of this Informed Consent form for your reference 
YES 
NO 
Do you freely accept to participate to this observational study, having understood the meaning of the request and 
the risks and benefits that it implies 
YES 
NO 
 
Signing this consent form, I freely consent to participate to the observational study indicated on top of this form, and to 
confer my data for the study, having understood the meaning of the request and the attending risks and benefits. 
Date:  .........................................  
 
Patient’s signature  ....................................................................................................................................  
Patient’s name and surname 
in block letters 
 
........................................................................................................................................................................ 
 
Date:  .........................................  
Signature of the Doctor who informed the patient 
............................................................................................................................................................................  
Doctor’s name and surname 
in block letters 
 
........................................................................................................................................................................ 
 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 30 of 45 
Appendix III – Declaration of new recruitment according to protocol 
 
To the Promoter of the WHITE Study (Arianna Anticoagulation Foundation) 
 
Country: 
 ...............................................................................................................................................  
 
Centre 
 ...............................................................................................................................................  
 
Please be informed that I have recruited the patient with WHITE code: 
 .............................................  
I declare under my responsibility that, based on the document archived at the centre: 
1. The subject presents all the required inclusion criteria; 
2. The subject is exempt of any exclusion criterion; 
3. The subject has signed the informed consent, which is archived in this centre. 
 
Signed: 
Dr. (full name in capital letters) 
 ......................................................................................  
 
 
signature: 
 ......................................................................................  
 
 
site and date: 
 ......................................................................................  
 
Please send this form by fax to: + 39 051 343604 or by email to <monitor.white@ariannafoundation.org> 
as soon as you have completed the recruitment of a new subject. 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 31 of 45 
Appendix IV – CRF template 
BASELINE FORM 1/8 
Identification 
 
Centre: |_|_|_| (from system 
Consecutive number |_|_|_| 
ID (from system) |_|_|_|_|_|_|_| 
based on user/ 
in the centre: 
(proposed by system) 
 
password) 
 
NOTE: if >40 issue warning 
 
Date of this visit (dd/mm/yyyy): |_|_|/|_|_|/|_|_|_| 
 
Informed consent signed:  0-no [STOP] 
Consent date (dd/mm/yyyy): |_|_|/|_|_|/|_|_|_| 
 
1-yes 
[consent date must be <= date of visit] 
 
Date of birth: |_|_|/|_|_|/|_|_|_| 
Age: |_|_|_| 
(dd/mm/yyyy) 
[computed by system; consent minus birth; must be >=18 years] 
 
Ethnicity:  1-White 
Specification:  
…………………………………………………………………… 
Sex:  
0-Female 
2-Black 
[if Ethnicity=7] 
 
 
1-Male 
3-Asian 
 
 
 
9-N/A 
4-Latino 
5-Native American (both North and South) 
6-Arabic 
7-Other (specify) 
9-N/A 
 
Index episode of venous thromboembolism 
 
Date of diagnosis: |_|_|/|_|_|/|_|_|_| 
Type of event:  (only one option among:) 
(dd/mm/yyyy) 
1=proximal or proximal plus distal DVT of lower limbs 
[must be 90-360 days before consent] 
2=isolated distal DVT of lower limbs 
 
3=DVT of lower limbs plus pulmonary embolism 
 
4=pulmonary embolism without deep vein thrombosis 
 
 
IN CASE OF DEEP VEIN THROMBOSIS: 
VEIN .............. left ........... right 
location of the index episode:  
external iliac ...............  .............  
(select all what applicable) 
common femoral ...............  .............  
[only if type=1, 2 or 3;  
superficial femoral ...............  .............  
at least one must be checked;  
deep femoral ...............  .............  
if both right and left are checked, request  
popliteal ...............  .............  
confirmation]  
posterior tibial ...............  .............  
[0=no; 1=yes] 
peroneal ...............  ............. 
 
anterior tibial ...............  .............  
 
medial gastrocnemius ...............  .............  
 
lateral gastrocnemius ...............  .............  
 
soleal ...............  .............  
 
saphenous (great and/or small) ...............  .............  

WHITE Study Protocol – Final Version – 20 September 2017 
p. 32 of 45 
BASELINE FORM 2/8 
Index episode of venous thromboembolism 
additional information 
 
Superficial vein thrombosis: 
 0-no 
 
 
1-yes 
 
In case of pulmonary embolism: 
Recent (1 month) echocardiography:  
If yes: date |_|_|/|_|_|/|_|_|_| 
 
 
0=no/1-yes – is NA with date blank if Type of event = 1 or 2 
 
Signs of pulmonary hypertension: 
 
 
 
0=no/1-yes – is NA with date blank if Type of event = 1 or 2 
 
 
HELP BOX: “PULMONARY HYPERTENSION” 
 
THE INDEX EVENT WAS ASSOCIATED WITH: 
 
surgery 
 
0-no; 1-yes 
 
severe trauma 
 
0-no; 1-yes 
 
cancer 
 
0-no; 1-yes 
 
motor function impairment (paraplegia) 
 
0-no; 1-yes 
 
limb immobilization in the 3 months before the event 
 
0-no; 1-yes 
 
central venous catheter 
 
0-no; 1-yes 
 
chronic inflammatory disease 
 
0-no; 1-yes 
 
bed rest >4 days 
 
0-no; 1-yes 
 
pregnancy 
 
0-no; 1-yes; 9-N/A 
 
puerperium 
 
0-no; 1-yes; 9-N/A 
 
obesity 
 
0-no; 1-yes  
 
heart failure 
 
0-no; 1-yes  
 
nephrotic syndrome 
 
0-no; 1-yes  
 
thrombophilia 
 
0-no; 1-yes;  
 
polycythemia/thrombocythemia 
 
0-no; 1-yes  
 
antiphospholipid antibody 
 
0-no; 1-yes  
 
estrogens and/or progestins 
 
0-no; 1-yes  
 
atrial fibrillation 
 
0-no; 1-yes  
 
inferior vena cava filter 
 
0-no; 1-yes 
 
long travel (> 4 h)  
 
0-no; 1-yesì 
 
other (specify) 
 
0-no; 1-yes 
 
other; specification 
 ................................................................................. 
 
 
 
The index thromboembolic event was: 
idiopathic ⃝ 
 
secondary ⃝ 
 
(only one choice; radio-button type) 
 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 33 of 45 
 
HELP BOX PULMONARY HYPERTENSION – FOR DATABASE USE ONLY 
 
Echocardiographic probability of pulmonary hypertension in symptomatic patients with a suspicion of 
pulmonary hypertension 
Peak tricuspid regurgitation 
velocity (m/s) 
Presence of other echo 
‘PH signs’ [a] 
Echocardiographic probability 
of pulmonary hypertension 
≤2.8 or not measurable 
No 
Low 
≤2.8 or not measurable 
Yes 
Intermediate 
2.9–3.4 
No 
2.9–3.4 
Yes 
High 
>3.4 
Not required 
PH = pulmonary hypertension 
[a] see table below 
 
Echocardiographic signs suggesting pulmonary hypertension used to assess the probability of pulmonary 
hypertension in addition to tricuspid regurgitation velocity measurement 
A: The ventricles [a] 
B: Pulmonary artery [a] 
C: Inferior vena cava and right 
atrium [a] 
Right ventricle/ left ventricle 
basal diameter ratio >1.0 
Right ventricular outflow 
Doppler acceleration time 
<105 msec and/or midsystolic 
notching 
Inferior cava diameter >21 mm 
with decreased inspiratory collapse 
(<50 % with a sniff or <20 % with 
quiet inspiration) 
Flattening of the interventricular 
septum (left ventricular 
eccentricity index >1.1 in systole 
and/or diastole) 
Early diastolic pulmonary 
regurgitation velocity >2.2 
m/sec 
Right atrial area (end-systole) >18 
cm2 
 
PA diameter >25 mm. 
 
PA = pulmonary artery 
[a] Echocardiographic signs from at least two different categories (A/B/C) from the list should be present to 
alter the level of echocardiographic probability of pulmonary hypertension. 
 
Ref: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European 
Society of Cardiology (ESC) and the European Respiratory Society (ERS) Endorsed by: Association for 
European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung 
Transplantation (ISHLT). 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary 
hypertension. European Heart Journal 2016: 37, 67-119. doi:10.1093/eurheartj/ehv317 
 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 34 of 45 
BASELINE FORM 3/8 
 
Clinical condition of veins 
 
Recent (1 month) compression ultrasound:  0-no 
If yes: date |_|_|/|_|_|/|_|_|_| 
 
1-yes 
 
Extent of residual thrombosis: 
LOCATION .............. left ........... right 
(mark all locations with extent 40% of diameter or 4 mm):  
external iliac ...............  .............  
0-no; 1-yes; default=no; if all=no and ultrasound=yes, ask confirmation 
groin ...............  .............  
 
middle of thigh ...............  .............  
 
popliteal area ...............  .............  
 
distal deep veins ...............  .............  
 
Presence of:  
varicose veins: 
 0-absent; 1-present; default: absent 
 
post-thrombotic syndrome:  0-absent; 1-present; default: absent 
 
oedema: 
 0-absent; 1-present; default: absent 
 
lipodermatosclerosis: 
 0-absent; 1-present; default: absent 
 
ulcer: 
 0-absent; 1-present; default: absent 
 
 
 
[check: if ulcer present, PTS must be present] 
 
Villalta score: 
Symptom/clinical signs 
none 
mild moderate 
severe 
 
 
default: 0 
=0 
=1 
=2 
=3 
 
Symptoms 
 
 
pain 
⃝ 
⃝ 
⃝ 
⃝ 
 
 
cramps 
⃝ 
⃝ 
⃝ 
⃝ 
 
 
heaviness 
⃝ 
⃝ 
⃝ 
⃝ 
 
 
paresthesia 
⃝ 
⃝ 
⃝ 
⃝ 
 
 
pruritus 
⃝ 
⃝ 
⃝ 
⃝ 
 
Clinical signs 
 
 
pretibial edema 
⃝ 
⃝ 
⃝ 
⃝ 
 
 
skin induration 
⃝ 
⃝ 
⃝ 
⃝ 
 
 
hyperpigmentation 
⃝ 
⃝ 
⃝ 
⃝ 
 
 
redness 
⃝ 
⃝ 
⃝ 
⃝ 
 
 
venous ectasia 
⃝ 
⃝ 
⃝ 
⃝ 
 
 
pain on calf compression 
⃝ 
⃝ 
⃝ 
⃝ 
 
Total score: |_|_| [computed from system: sum of all the above marks; ranges 0 to 33] 
 
[system computes and stores classification of PTS; absent if 0-4; mild if 5-9; moderate if 10-14; 
 
severe if 15 or more or if ulcer from previous box is marked present] 
 
[check: if Villalta >=5 and post-thrombotic syndrome is marked absent, issue a warning] 
 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 35 of 45 
BASELINE FORM 4/8 
 
Concurrent diseases at this visit 
 
History of cancer .................................   0-no; 1-yes; default=no 
Active cancer .......................................   
if yes:  
with metastases: 
 0-no; 1-yes 
 
  
 
under chemotherapy:  0-no; 1-yes 
Diabetes ..............................................   
Hypertension .......................................   
TIA/stroke/peripheral embolism ........   
Ischemic heart disease ........................   
Left ventricular hypertrophy ...............   
Heart failure ........................................   
Peripheral vascular disease .................   
History of angioplasty/surgery............   
Chronic inflammatory diseases ...........   
Chronic respiratory diseases ...............   
Cirrhosis + esophageal varices ............   
Kidney failure ......................................   
Hypothyroidism...................................   
Hyperthyroidism .................................   
Other diseases ....................................   
 
Current medications (used for at least 3 months) at this visit 
 
ASA <250 mg/day ................................   0-no; 1-yes [default=no] 
Other antiplatelets ..............................   
Antiarrhythmic agents ........................   
Antidiabetics .......................................   
Antidyslipidemic agents ......................   
ACE inhibitors ......................................   
Sartans ................................................   
Beta-blockers ......................................   
Diuretics ..............................................   
Calcium antagonists ............................   
Other antihypertensive agents ...........   
Nitrates ...............................................   
Digitalis ................................................   
Proton pump inhibitors .......................   
Antiviral agents ...................................   
Immunosuppressives ..........................   
Steroids ...............................................   
Drugs for thyroid disorders .................   
Analgesic agents .................................   
Anti-inflammatory drugs .....................   
 
 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 36 of 45 
BASELINE FORM 5/8 
 
Vascular risk factors at this visit 
 
Smoking ...............................................   0-no; 1-yes; 9-N/A 
if yes: less than 10 cigarettes per day 
⃝ 
 
  
 
10-20 cigarettes per day 
⃝ 
 
  
 
more than 20 cigarettes per day ⃝ 
Thrombophilia test..............................   0-negative; 1-positive; 9-not done 
if positive: specify which ....................................................................Factor V Leiden 
 
 
  
 
Factor II G20210A 
 
 
  
 
Protein C deficiency 
 
 
  
 
Protein S deficiency 
 
 
  
 
AT deficiency 
 
 
  
 
LAC+aCL Anti-Beta2GP1 
 
 
  
 
Hyperhomocysteinemia 
 
 
  
 
JAK2 
 
 
  
 
other 
 
 
  
 
(specify other) .................................. 
 
  
 
[0-negative; 1-positive; 9-not done; default: N/A] 
 
Dementia (assumed absent unless there is evidence it is present)... 0-no; 1-yes 
Chronic bed rest ................................................................................. 
Wheelchair ......................................................................................... 
Tendency to falls ................................................................................ 
History of major bleeding .................................................................. if yes: 
 
cerebral hemorrhage 
 
 
  
 
gastrointestinal bleeding 
 
 
  
 
retroperitoneal hemorrhage 
 
 
  
 
ocular haemorrhage 
 
 
  
 
intra-articular haemorrhage 
 
 
  
 
hemoglobin drop by 2 or more g/dL  
 
  
 
transfusion 
 
Living alone ........................................................................................ 
Absence of family or social support ................................................... 
Family history of thromboembolism ................................................. 
Family history of coronary disease .................................................... 
Family history of TIA/stroke ............................................................... 
Alcohol consumption ......................................................................... if yes: 1 unit per day 
⃝ 
1 unit = 1 glass (125 ml) of wine or 1 can 
 
2 units per day 
⃝ 
(330 ml) of beer or 1 tumbler (30 ml) of spirit 
 
more than 2 units per day ⃝ 
 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 37 of 45 
BASELINE FORM 6/8 
 
Other clinical information 
 
Body weight (kg): |_|_|_|.|_| 
height (cm): |_|_|_| 
BMI: |_|_|.|_| 
check limits: 40-200 
check limits: 90-230 
computed: kg/m2 
 
If available: last creatinine value recorded during the 3 months before the visit: 
Creatinine: units ⃝ mg/dL (default) 
value: |_|_|.|_|_|_| 
clearance: |_|_|_|.|_| 
 
⃝ mol/L 
 
computed; Cockroft-Gault formula 
if creatinine is in mol/L multiply by 0.01131222; round to 3 digits 
clearance (in mL/min): 
 
 
 
Maintenance anticoagulation treatment prescribed after the index event 
(the treatment to continue-resume/stop/change at this visit) 
 
Treatment start date (dd/mm/yyyy): |_|_|/|_|_|/|_|_|_|_| [check: must be >= Date of diagnosis] 
 
 
[if (visit minus start) <90 days or >360 days, warning] 
 
Treatment actual stop date (dd/mm/yyyy): |_|_|/|_|_|/|_|_|_|_| 
[check: must be <=Date of this visit] 
 
 
[and >= Date of this visit minus 30 days] 
 
Treatment prescribed: 
vitamin-K antagonist 
 
0-no; 1-yes; if yes open window VKA 
[one MUST be selected] 
low molecular weight heparin 
 
0-no; 1-yes; if yes open window LMWH 
 
direct anticoagulants (NOACs) 
 
0-no; 1-yes; if yes open window NOACS 
 
other 
 
0-no; 1-yes; if yes open window below 
 
[if “other”=yes] specify other (common name):  ...............................................................  [text] 
 
daily dose:  .................... 
dose units:  ................................... ATC if known: |_|_|_|_|_|_|_| 
 
[number, floating point] 
[text] 
[text] 
 
 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 38 of 45 
 
WINDOWS FOR CLASS VKA, LMWH, NOACS – FOR DATABASE USE ONLY 
The following tables are called-in upon selection of the drug class. 
The operator can select one only from each of these, and is requested to input the daily dose as number 
CHECK supplies the acceptable range for the number. Doses out of range require a warning- 
TO BE RECORDED: ATC CODE and DAILY DOSE. There should be not more than one per class (VKA, LMWH, 
NOAC); two of them may be empty if OTHER is empty; all three can be empty if OTHER is marked. 
 
VKA 
Name 
unit 
DAILY DOSE 
ATC code 
CHECK 
dicoumarol 
mg 
 
B01AA01 
25-400 
phenindione 
mg 
 
B01AA02 
25-400 
warfarin 
mg 
 
B01AA03 
1.25-30 
phenprocoumon 
mg 
 
B01AA04 
0.5-12 
acenocoumarol 
mg 
 
B01AA07 
1.25-20 
ethyl biscoumacetate 
mg 
 
B01AA08 
125-2400 
LMWH 
Name 
unit 
DAILY DOSE 
ATC code 
CHECK 
bemiparin 
Ux1,000 
 
B01AB12 
5-10 
certoparin 
Ux1,000 
 
B01ABXX 
8-16 
dalteparin 
Ux1,000 
 
B01AB04 
0.15-18 
enoxaparin 
Ux1,000 
 
B01AB05 
6-15 
nadroparin 
Ux1,000 
 
B01AB06 
3-8.5 
parnaparin 
Ux1,000 
 
B01AB07 
4-12.8 
reviparin 
Ux1,000 
 
B01AB08 
5-10.5 
tinzaparin 
U/kg 
 
B01AB10 
>=175 
NOACS 
Name 
unit 
DAILY DOSE 
ATC code 
CHECK 
rivaroxaban 
mg 
 
B01AF01 
5-30 
apixaban 
mg 
 
B01AF02 
5-20 
edoxaban 
mg 
 
B01AF03 
30-60 
dabigatran 
mg 
 
B01AE07 
220-300 
 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 39 of 45 
BASELINE FORM 7/8 
 
Decision on next therapy 
 
From this visit onward, the therapy will be: 
⃝ continued with same anticoagulant 
if yes specify: at the same dose: ⃝ 0 
 
 
 
 
at reduced dose:   ⃝ 1 
 
 
 
 
dose units:  ...................... 
total daily dose: |_|_|_|.|_| 
 
 
 
 
 
[text] 
 
[number, floating point] 
⃝ continued with an anticoagulant of the same class 
open the box “replaced_1”. 
⃝ replaced by an anticoagulant of a different class 
open the box “replaced_1”. 
⃝ replaced by another class of antithrombotic 
open the box “replaced_2”. 
⃝ discontinued without replacement 
 
one and only one of these choices MUST be selected 
 
Please specify: 
Treatment prescribed in this visit: 
Box “replaced_1” 
 
vitamin-K antagonist 
 
0-no; 1-yes; if yes open window VKA 
 
low molecular weight heparin  
0-no; 1-yes; if yes open window LMWH 
 
direct anticoagulants (NOACS)  
0-no; 1-yes; if yes open window NOACS 
 
other 
 
0-no; 1-yes; if yes open window “other” 
 
 
Treatment prescribed in this visit: 
Box “replaced_2” 
 
aspirin 
 
0-no; 1-yes 
 
if aspirin=yes: 
daily dose: 
⃝ 75-175 mg 
 
ATC: B01AC06 
 
 
⃝ 176-250 mg 
 
 
 
 
⃝ 251-500 mg 
 
 
 
 
⃝ >500 mg 
 
sulodexide 
 
0-no; 1-yes 
 
if sulodexide = yes: 
daily dose: 
⃝ 500 LSU 
 
ATC: B01AB11 
 
 
⃝ 1000 LSU 
 
other 
 
0-no; 1-yes; if yes open window “other” 
 
 
 
 
 
Box “other” 
[if “other”=yes] specify other (common name): .............................................................  [text] 
 
daily dose: .................   
dose units:  ................... 
ATC if known: |_|_|_|_|_|_|_| 
 
[number, floating point] 
[text] 
[text] 
 
Please specify whether compression therapy is prescribed: 
 
no: 
⃝ 0 
 
yes: 
⃝ 1 
specify mmHg recommended: |_____| [text] 
 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 40 of 45 
BASELINE FORM 8/8 
 
Reasons for taking this decision 
(please tick all what applicable) 
 
No need of further treatment 
 0-no; 1-yes; default=no 
Risk of thromboembolic recurrence 
 
specify: 
⃝ high-medium 
 
 
 
 
⃝ low 
 
 
 
 
[HELP BOX FOR CRITERIA] 
Risk of bleeding 
 
specify: 
⃝ high 
 
 
 
 
⃝ medium 
 
 
 
 
⃝ low 
 
 
 
 
[HELP BOX FOR CRITERIA] 
Major bleeding event during treatment 
 
Difficulty to maintain the proper INR 
 
Consideration of patient's age 
 
Presence of Post Thrombotic Syndrome 
 
Presence of thrombophilia 
 specify: ________________________________ [text] 
Familiarity for venous thromboembolism 
 
Implantation of vena cava filter 
 
Presence of pulmonary hypertension 
 
Worsening of general conditions (not cancer)  
Worsening/onset of renal insufficiency 
 
Tendency to falls 
 
Presence of cancer 
 
Onset of contraindications 
 specify: ________________________________ [text] 
Decision by the patient’s family doctor 
 
Choice of the patient 
  
Cost for the patient 
 
Positive D-dimer value 
 specify value: |_|_|_| D-DU ⃝       FEU ⃝ 
Negative D-dimer value 
 specify value: |_|_|_| D-DU ⃝       FEU ⃝ 
 
[if D-dimer value specified, one of the units MUST be specified] 
 
Patient involved in choosing the prescribed therapy 
 0-no; 1-yes; default=no 
Patient’s GP involved in choosing the prescribed therapy 
 0-no; 1-yes; default=no 
 
Planned duration of this therapy: ⃝ not applicable [if decision=2, only possible choice] 
 
⃝ not defined 
 
⃝ to be evaluated 
 
⃝ defined; specify: |_|_|_| 
⃝ months 
 
 
 
⃝ years 
 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 41 of 45 
FOLLOW-UP FORM 1/3 
SECTION 2 – FOLLOW-UP 
The follow-up is intended for up to 2 years, with total maximum 8 contacts plus unpredictable number of unplanned contacts (few). 
 
Interview ID 
 
ID (from system) ................................. |_|_|_|_|_|_|_| 
[obtained from database based on username/password  
 
  
and number within center] 
Nominal contact time (month): |_|_| [options: 3-6-9-12-15-18-21-24 plus 9# (starting from 90  
 
and increased by 1 at each new unplanned visit: unplanned 
 
proposed by system, can be replaced. CHECK: baseline must be present; conclusion must 
 
not be present. Investigator informed forty days in advance by mail. If not completed 
 
within 2 weeks from due date, new mail to the investigator. For visits 12-and 24 the 
 
mail should indicate that a visit at the center should be planned.] 
Date of contact (dd/mm/yyyy): |_|_|/|_|_|/|_|_|_|_| 
Type of contact: 
 1=telephone call; 
if type=2: Type of visit:  
1=planned by investigator 
 
 
2=visit at center 
 
 
 
2=planned, requested by patient 
 
 
 
 
 
 
3=unplanned 
 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 42 of 45 
FOLLOW-UP FORM 2/3 
 
Events occurred after last interview 
[check: if any left box is marked “yes”, there MUST be a right box marked “yes”or date/reason] 
 
Thrombotic complications: 
 
0-no 
if yes, specify: deep vein thrombosis 
 0-no; 1-yes; default=no 
 
 
1-yes 
 
pulmonary embolism 
 
 
 
 
 
superficial vein thrombosis 
 
 
 
 
 
transient ischemic attack (TIA)  
 
 
 
 
ischemic stroke 
 
 
 
 
 
acute myocardial infarction 
 
 
 
 
 
sudden/cardiac death 
 [CHECK death below] 
 
 
 
 
other; specify 
  
 
 
 
 
 _____________________________________  [text] 
 
Bleeding complications: 
 
0-no; 1-yes; default=no 
if yes, specify how many: 
 
 
 
|_|_| 0; if bleeding complication=yes, should be 1 
if yes, specify: 
type of complication: 
 major bleeding 
 
 
 
 
 clinically relevant non-major bleeding 
 
 
 
 
 other bleeding 
 
 
 
 
N/A; if bleeding complication = yes, at least one should be indicated 
 
 
 
 
HELP BOX BLEEDING CLASSIFICATION 
 
if yes, specify the nature of the complication: 
cerebral hemorrhage/hemorrhagic stroke  
 
 
 
 
gastrointestinal hemorrhage 
 
 
 
 
 
retroperitoneal hemorrhage 
 
 
 
 
 
intra-ocular hemorrhage 
 
 
 
 
 
retinal bleeding 
 
 
 
 
 
intra-articular hemorrhage (hemarthrosis)  
 
 
 
 
hemoglobin drop by 2 or more g/dL 
 
 
 
 
 
transfusion of 2 or more units 
 
 
 
 
of red cell concentrate 
 
 
 
 
 
uterine bleeding 
 
 
 
 
 
skin/muscle hematoma 
 
 
 
 
 
nose bleed 
 
 
 
 
 
bleeding gums 
 
 
 
 
 
anal bleeding 
 
 
 
 
 
other; specify 
  
 
 
 
 
 _____________________________________  [text] 
 
Hospitalization: 
 
0-no  
if yes, specify: date (dd/mm/yyyy) |_|_|/|_|_|/|_|_|_|_| 
 
 
1-yes 
 
reason: ______________________________  [text] 
 
Patient’s death: 
 
0-no  
if yes, specify: date (dd/mm/yyyy) |_|_|/|_|_|/|_|_|_|_| 
 
 
1-yes 
 
reason: ______________________________  [text] 
 
Any other event preventing  
0-no  
if yes, specify: date (dd/mm/yyyy) |_|_|/|_|_|/|_|_|_|_| 
continuation of the follow-up 
1-yes 
 
reason: ______________________________  [text] 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 43 of 45 
 
HELP BOX BLEEDING 
 
1. A major bleeding is defined as having a symptomatic presentation and: 
• is fatal, and/or 
• occurs in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, 
intraarticular or pericardial, or intramuscular with compartment syndrome, and/or 
• causes a fall in hemoglobin level of 20 g/L (1.24 mmol/L) or more, or leads to transfusion of two or 
more units of whole blood or red cells. 
2 A clinically relevant non-major bleeding is defined as 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 definition of major bleeding above, but does meet at least one of the 
following criteria:  
• requiring medical intervention by a healthcare professional;  
• leading to hospitalization or increased level of care;  
• prompting a face to face (i.e., not just a telephone or electronic communication) evaluation. 
3. All bleedings that do not meet definition 1 or definition 2 are classified as “other”. 
 
Reference: Kaatz S, Ahmad D, Spyropoulos AC, Schulman S, for the Subcommittee on Control of 
Anticoagulation. 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. 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 44 of 45 
FOLLOW-UP FORM 3/3 
Antithromboembolic therapy 
 
There was any change in the prescribed anti-thromboembolic therapy 
after the last contact (in the last 3/6 months)? 
 0-no; 1-yes 
 
If yes, the therapy was: 
 
dose reduced (not discontinued): 1 
 
 
dose increased: 2 
 
 
newly instituted: 3 
 
 
discontinued without replacement: 4 
 
 
replaced with another therapy: 5 
 
 
[if change=0, blank; if change=1 MUST be filled; 
 
 
if replaced, continue with boxes below] 
Specify if change was decided by: 
⃝ investigator or co-investigator 
 
⃝ other physician 
 
⃝ spontaneously by patient 
 
If replaced with another therapy, please specify: 
Treatment switched to: 
 
vitamin-K antagonist 
 
0-no; 1-yes; if yes open window VKA 
 
low molecular weight heparin  
0-no; 1-yes; if yes open window LMWH 
 
direct anticoagulants (NOACS)  
0-no; 1-yes; if yes open window NOACS 
 
aspirin 
 
0-no; 1-yes 
 
if aspirin=yes: 
daily dose: 
⃝ 75-175 mg 
 
ATC: B01AC06 
 
 
⃝ 176-250 mg 
 
 
 
 
⃝ 251-500 mg 
 
 
 
 
⃝ >500 mg 
 
sulodexide 
 
0-no; 1-yes 
 
if sulodexide = yes: 
daily dose: 
⃝ 500 LSU 
 
ATC: B01AB11 
 
 
⃝ 1000 LSU 
 
other 
 
0-no; 1-yes; if yes open window below 
 
[if “other”=yes] specify other (common name):  ...............................................................  [text] 
 
daily dose:  .................... 
dose units:  ................................... ATC if known: |_|_|_|_|_|_|_| 
 
[number, floating point] 
[text] 
[text] 
 
 
 
DECISION: in case of 
a) thrombotic complication; 
b) death  
c) event preventing continuation 
d) newly instituted therapy 
e) discontinued therapy 
f) change to new therapy 
go to END-OF-TRIAL. 
 
IN CASE OF: 
a) bleeding complication 
b) hospitalization, ASK if patient remains on trial or goes to END-OF-TRIAL. 
 

WHITE Study Protocol – Final Version – 20 September 2017 
p. 45 of 45 
END-OF-STUDY FORM 
SECTION 3 – CONCLUSION – END-OF-TRIAL form 
 
Patient’s end-of-study information 
 
ID (from system) ................................. |_|_|_|_|_|_|_| 
[obtained from database based on username/password  
 
  
and number within center] 
Date of form completion (dd/mm/yyyy): |_|_|/|_|_|/|_|_|_|_| [obtained from system] 
 
Reason for concluding the follow-up of this patient 
 
The patient reached the end of the planned observation period 
 date: |_|_|/|_|_|/|_|_|_|_| 
 
 
0-no; 1-yes; default=no  
exact date: dd/mm/yyyy 
Showed a thromboembolic event 
 
  
date: |_|_|/|_|_|/|_|_|_|_| 
Showed a major bleeding event 
 
 
  date: |_|_|/|_|_|/|_|_|_|_| 
Had a major change in therapy 
 
 
  date: |_|_|  |_|_|/|_|_|_|_| 
Reported another event preventing continuation of the follow-up 
  date: |_|_|  |_|_|/|_|_|_|_| 
 
 
 
 
these dates may be incomplete (no day) 
The patient died 
 
 
  date: |_|_|/|_|_|/|_|_|_|_| 
The patient reported to another hospital 
 
  date: |_|_|  |_|_|/|_|_|_|_| 
The patient moved to another place  
 
  date: |_|_|  |_|_|/|_|_|_|_| 
The patient was lost to follow-up 
 
 
  date: |_|_|  |_|_|/|_|_|_|_| 
 
 
CHECK: at least one must be marked yes; if thromboembolic event is marked, there must be a thromboembolic event in the last 
follow-up form; if bleeding event is marked, there must be a bleeding event in the last follow-up form, items 1-9; if died is marked, 
there should be death=yes in last follow-up form, if other event is marked, there must be a “other event” marked in the last follow-
up form. 
After this form is concluded, the case is closed and cannot be modified by the users. It can be re-opened upon request (ticket), 
endorsed by the study supervisors.