Multicenter Observational Program Evaluation of the Efficacy and Tolerability of Detralex Treatment in Patients With Chronic Venous Edema (CEAP Class С3) in Real Clinical Practice
Conditions: Chronic Venous Disease
Sponsor: Servier Russia

1 
 
 
 
 
 
 
Multicenter observational program  
VAP-PRO-C3 
Protocol n° IC4-05682-055-RUS 
 
NCT03722836    
 
Evaluation of the efficacy and safety of vasoactive drugs as a part of 
combination treatment, and its influence on the general outcomes of 
treatment of patients with chronic venous edema (CEAP class C3) in real 
clinical practice. 
 
01\09\2018 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

2 
 
 
Background 
An edema takes a special place among clinical manifestations of varicose veins of the lower 
extremities. Its occurrence suggests about significant hemodynamic disorders, the consequence 
of which is a cascade of pathological reactions at the microcirculatory and molecular levels.1,2 
Clinical significance of this sign of the disease is illustrated by the fact that such a widely 
known term as “chronic venous insufficiency” (CVI) is applied already at the occurrence of 
venous edema (CEAP class C3).3 For several decades, the pathogenetic aspects of venous 
edema, as well as the issues of treatment of CVI patients have been a subject of active 
investigations worldwide. To date, the mechanisms leading to the development of edema have 
been explored,4 the complex of measures for treating patients with C3 clinical class was 
established, and the efficacy of such a treatment was confirmed. At the same time, studies in 
CVI are ongoing, and many problems still await their solution. In particular, one of them relates 
to a search for an optimal method of diagnosis and conservative treatment of the disease. 
 
References 
1. Nicolaides N., Allegra C., Bergan J. et al. Management of Chronic Venous Disorders of the 
Lower Limbs. Guidelines According to Scientific Evidence. Int Angiol 2008; 27:1-59.  
2. Handbook of venous disorders. Guidelines of the American Venous Forum (third edition). 
Edited by P. Gloviczki. Hodder Arnold 2009; ISBN -978-0-340-938-805. 
3. Coleridge Smith Ph.D. Microcirculation in Venous Disease (second edition). LANDES 
bioscience 1998; ISBN- 1-57059-476-7. 
4. Bergan J.J., Shortell C.K. Venous ulcers. ELSEVIER 2007; ISBN-13:978-0-12-373565-2. 
 
Design 
The VAP-PRO-C3 is a multicenter observational program, which is carried out in the frame of 
routine consultations and follow-up of patients. The program includes patients with chronic 
venous diseases (CVDs) of CEAP class C3. It is scheduled in Russia for 2018-2019. The 
program is expected to enroll 90 phlebologists from 60 cities of Russia. The planned number of 
patients is 1350.  
   
First visit of the first patient:  
 
  01\10\2018 
Last visit of the last patient:  
 
  30\03\2019 
Completion of statistical analysis: 
 
  30\04\2019 
Preliminary report: 
 
 
 
  20\08\2019 
Final report:  
 
 
 
  30\03\2020 
 
Aim of the study 
The study is aimed at evaluating the efficacy and safety of systemic pharmacotherapy 
(Detralex) as a part of combination treatment, and its influence on the general outcomes of 
treatment of patients with chronic venous edema (CEAP class C3) in real clinical practice. 
 
Methodology 
Each investigator is planned to include in the program 10 patients fulfilling the inclusion 
criteria. The treatment will be carried out in accordance to the routine clinical practice, 

3 
 
instructions for the medical use of drugs, and a specific clinical situation. To assess changes in 
edema, the method of truncated cones and duplex ultrasound scanning (DUS) will be used.  
In the case report form (CRF), only the data for the extremity with most pronounced edema 
will be recorded.  
 
Method of truncated cones: 
 
 
The method is based on the assumption that the shape of the lower extremity approaches the 
shape of several truncated cones connected by bases that coincide in area. The volume of the 
cone is calculated by measuring the circumference of the upper (C2) and lower (C1) cones and 
the height (h) between them. For calculating the volume of lower cone, the following formula is 
used: 
V = (p / 12p)²h (C2² + C2XC1 + C1²)=\__\\__\\__\ml 
The volume of the lower limb is determined by summing the volumes of all the cones. The 
smaller the height of the segments, the more accurate the result. 
 
Duplex ultrasound scanning: 
 
The thickness of subcutaneous fat in a standard point. 
Reflux or occlusion with indication of the pool                                                                                    
 
• The measurements should provide in the afternoon and, if possible, at the same time. At 
the Visit 0 (V0) and Visit 4 (V4) 
• The examination will be performed on both extremities.  
• In the CRF, only the data for the extremity with most pronounced edema will be 
recorded.  
• The standard point is 10 сm higher than medial malleolus 
 
The present study does not imply any change in the usual management of patients with CVD. 
In particularly, the study will record indicators that are usually evaluated during the 

4 
 
examination of patients with CEAP class C3 of CVD. Particular attention will be paid to 
determining the changes of edema using the routine methods (geometric method of a truncated 
cones and duplex ultrasound scanning). 
 
Treatment 
The observational nature of the program assumes that all examinations, procedures and changes 
in the therapy of a patients, including changes in doses of drugs, should be carried out only on 
the basis of the decision of attending physician and in full accordance with the current 
guidelines for management of a particular type of patients under investigation, instructions for 
medical use of the drugs, as well as in the settings of routine practice. 
 
The treatment is carried out in full accordance with the current guidelines. Participation of a 
patient in the program, as well as his/her refusal to continue participation, should not affect the 
current treatment, the availability of diagnostic procedures, or the amount and quality of other 
necessary medical care. Names and doses of drugs used for the CVD treatment, as well as 
changes in the doses will be recorded in the CRF. 
 
Inclusion criteria: 
• Age 18 years old or above 
• Written informed consent 
• Patient did not receive treatment with venoactive drugs within the past 4 weeks prior to 
the inclusion in the study 
• Diagnosis of chronic venous disease of class C3 (CEAP)  
• Doctor plan to prescribe VADs 
 
Exclusion criteria: 
• Age below 18 years old 
• Written informed consent is not obtained 
• History of alcohol or drug abuse or use of narcotic drugs 
• History of allergic reaction to diosmin or any other venoactive agent, or their 
intolerance 
• History of allergic reaction to anesthetics and/or sclerosing agents 
• Chronic venous disease of СЕАР class C0-С2 or class С4-С6 
• Lymphatic edema of the lower extremities 
• Secondary varicose veins, angiodysplasia, or neoplasia 
• Arterial disease (ankle-brachial index <0.9) 
• Infection within the past 6 weeks 
• Any of the following concomitant diseases, which can affect the results: 
o Connective tissue disease (including rheumatoid arthritis), arthritis 
o Heart failure 
o Chronic kidney disease 
o Intermittent claudication (peripheral artery disease) 
o Diseases of the bones or joints of the lower extremities  
o Malignant growth  

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• Treatment with drugs potentially causing leg edema (calcium channel blockers, 
hormonal drugs, NSAIDs, etc.) 
• History of deep vein thrombosis (within the past year) 
• History of superficial thrombophlebitis (within the past 3 months) 
• Patient cannot walk (regardless of the cause) 
• Predictable poor adherence to treatment 
• Participation of the patient in the intervention study within the previous 3 months 
• For women: pregnancy or breastfeeding, the desire to become pregnant within at least 2 
months after the study  
• Patient cannot attend a follow-up visit 
• Patients with a contraindication to diosmin-containing agents, including Detralex 
 
Criteria for the assessment of treatment efficacy 
1. Venous clinical severity score (VCSS).5 
2. Clinical class of CVD according to CEAP classification.6 
3. Changes in the severity of CVD symptoms (leg heaviness, pain, swelling, night cramps 
and itching), as assessed by the visual analogue scale (VAS).7 
4. Changes in the severity of edema, as assessed by the method of truncated cones8 and 
duplex ultrasound scanning. 
5. Changes in the quality of life, as assessed by the CIVIQ-14 questionnaire.9 
6. Satisfaction with treatment, as assessed by the Darvall self-administered 
questionnaire.10 
 
 
References 
5. Rutherford R.B., Padberg F.T. Jr, Comerota A.J., Kistner R.L., Meissner M.H., Moneta G.L.; 
American Venous Forum’s Ad Hoc Committee on Venous Outcomes Assessment: Venous 
severity scoring: An adjunct to venous outcome assessment. J Vasc Surg 2000;31:1307-1312.  
6. Российские клинические рекомендации по диагностике и лечению хронических 
заболеваний вен. Савельев В.С., Покровский А.В., Затевахин И.И., Кириенко А.И. и др. 
Флебология. 2013;7(2):2-47. [The Russian clinical guidelines for the diagnosis and treatment 
of chronic venous diseases. Savelyev VS, Pokrovsky AV, Zatevakhin II, Kirienko AI et al. 
Flebologiya. 2013;7(2):2-47. (In Russ.).]  
7. Huskisson E.C. Measurement of pain. Lancet 1974; 2:1127-1131.  
8. Lennihan R.Jr, Mackereth M. Calculating volume changes in a swollen extremity from 
surface measurements. Am J Surg. 1973 Nov;126(5):649-52. 
9. Launois R., Mansilha A., Jantet G. International Psychometric Validation of the Chronic 
Venous Disease Quality of Life Questionnaire. Eur J Vasc Endovasc Surg. 2010;40:783-789. 
10. Darvall K.A.L., Bate G.R., Sam R.C., Adam D.J., Silverman S.H., Bradbury A.W. Patients’ 
expectations before and satisfaction after ultrasound guided foam sclerotherapy for varicose 
veins. Eur J Vasc Endovasc Surg 2009; 38:642-647. 
 
PLAN OF THE STUDY 
 
Procedure 
V0 visit 
V1 visit 
V2 visit 
V3 visit 
V4 visit 

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(Inclusion) 
 
(at 2 weeks) 
 
(at 1 month) 
 
(at 2 months) 
 
(at 3 months) 
 
Informed consent form 
+ 
 
 
 
 
 
Patient’s questionnaires 
+ 
 
 
 
+ 
Completion of the CRF  
+ 
+ 
+ 
+ 
+ 
VCSS 
+ 
 
 
 
+ 
CEAP 
+ 
 
 
 
+ 
Data on the treatment 
and its change 
 
+ 
 
+ 
 
+ 
 
+ 
 
+ 
Registration of AEs  
 
+ 
+ 
+ 
+ 
Assessment of edema by 
the method of truncated 
cones 
+ 
+ 
+ 
+ 
+ 
Assessment of edema by 
duplex ultrasound 
scanning (DUS) 
 
+ 
 
 
 
+ 
Detralex  
500 mg 2 times per day 
1000 mg daily (1 tablet 
or 1 sachet) 
+ 
+ 
+ 
+ 
+ 
Compression hosiery, 
topical treatment 
Compression therapy can be administered on discretion of investigator at any visit 
Surgical intervention 
 
Surgery can be performed on discretion of investigator at any visit 
 
Safety considerations 
 
1. Definitions 
1.1 Pharmacovigilance information  
Pharmacovigilance data include any unintended or adverse event associated with the use of a 
medicinal product in humans, whether or not considered drug related, including the following 
special situations (situations where no adverse event occurred but information needs to be 
collected): 
- exposure during pregnancy or breastfeeding;  
- overdose, abuse, misuse, off-label uses, medication error, occupational exposure (including 
professional one); 
- lack of the treatment efficacy of drug. 
 
1.2. Adverse event (AE)  
Adverse event (AE) is any untoward medical occurrence in a patient or clinical-trial participant 
who received the medicinal product, which does not necessarily have a causal relationship with 
the use of this medicinal product. 
An adverse event can therefore be any unfavourable and unintended sign (e.g. an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered as related to the medicinal product. 
 
1.3. Adverse (drug) reaction (ADR) 

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Adverse reaction (synonyms: Adverse drug reaction, Suspected adverse (drug) reaction, 
Adverse effect, Undesirable effect) is a response to a medicinal product which is noxious and 
unintended.  
“Response” in this context means that a causal relationship between a medicinal product and an 
adverse event is at least a reasonable possibility.  
Adverse reactions may arise from use of the product within or outside the terms of the 
marketing authorization or from occupational exposure. Conditions of use outside the 
marketing authorization include off-label use, overdose, misuse, abuse and medication errors. 
 
1.4. Serious adverse (drug) reaction (SADR)  
Serious adverse reaction is an adverse reaction, which results in death, is life-threatening, 
requires in-patient hospitalisation or prolongation of existing hospitalisation, results in 
persistent or significant disability or incapacity, or is a congenital anomaly/birth defect. 
Life threatening in this context refers to a reaction in which the patient was at risk of death at 
the time of the reaction; it does not refer to a reaction that hypothetically might have caused 
death if more severe. 
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
 
2. Responsibilities  
2.1. Events to be reported  
All available information about the following events reported during the study will be recorded:  
• All serious adverse drug reactions related to the use to Detralex 
• All non-serious adverse drug reactions related to the use to Detralex 
• All reports about special situations (see 1.1) 
• All adverse events 
 
2.2. Responsibilities of investigator  
In prospective studies, at medical visits the investigator will ask a participating patient to 
indicate whether or not an adverse event (serious or not) has occurred. 
Investigator has to assess causal relationship between an adverse event and the investigated 
drug intake, as well as the seriousness criteria and later on the outcome of the event.  
In case of Adverse Events, Adverse Drug Reactions or special situations that occurs during the 
study (both serious and non-serious), the investigator must complete the “Adverse event / 
Adverse drug reaction / Special Situation Reporting Form” (Appendix 1) without waiting 
for the clinical outcome or the results of additional investigations.  
If the event is serious, it will be notified immediately (same or next working day at the latest) to 
Servier company in Russia via e-mail to address pvmail.rus@servier.com or by fax to 

8 
 
number (495) 937-47-66. The anonymized copies of all the available and relevant laboratory 
findings, hospitalisation reports or other investigation results performed in connection with the 
adverse event should be attached to the form. 
All other events should be reported by investigator within 2 working days. 
The same rules apply for the transferring of additional information about the event.  
The investigator must ensure the appropriate follow-up of the patient depending on the nature 
of event, until it resolves. The investigator will continue to notify follow up data according to 
timeframes defined above. 
If investigator does not follow-up a patients anymore (i.e. in case of hospitalisation followed by 
the treatment by specialist or the participant's general practitioner,…), he/she will do every 
effort to contact the specialist or department in charge of follow-up of the patient, so as to have 
additional information and report it to Servier company in Russia. 
 
2.3. Responsibilities of sponsor/marketing authorization holder (MAH)  
Independently of the regulatory obligations of investigator, the sponsor/MAH must report the 
pharmacovigilance data to the appropriate authorities in accordance with the Good Vigilance 
Practice and local regulations. 
Cases are closed when an adverse event has recovered or patient’s condition was stabilized and 
the report is deemed sufficiently detailed for adequate medical analysis of the case. 
 
Statistical parameters 
Statistical analysis: 
Baseline characteristics will be analyzed in all included patients despite adherence to the 
protocol. Analysis of the results of program will be performed using the SPSS 12.0 software 
package (SPSS Inc., USA). The data entry errors will be corrected before the statistical 
processing. Quantitative parameters will be presented, depending on the distribution of raw 
data, as arithmetic mean ± standard deviation for parametric variables, or as median (25; 75 
percentiles) for nonparametric variables. Multiple comparisons will include adjustments for 
continuity.  
Changes in the quantitative parameters during the follow-up period will be evaluated using the 
Student's t-test for paired samples or its nonparametric analogue, Wilcoxon test. Differences on 
the quantitative parameters, both between the independent groups and during the follow-up, 
will be evaluated as the mean difference with the corresponding 95% confidence interval. 
Intergroup comparisons of changes in VAS scores, global index of CIVIQ questionnaire, 
Darvall index, and an integral score of the edema severity will be carried out using two-factor 
analysis of variance (ANOVA) with repeated measures to compare the scores before and after 
the treatment. 
Safety will be assessed in the intention-to-treat population (all patients who received at least 
one dose of Detralex during the study). 
Adverse events will be recorded and analyzed in patients with the reporting of all the AEs, 
SAEs, ADRs, SADRs and special situations. 
 
 
Patient’s expectations and satisfaction with the treatment 

9 
 
After adjustments for the confounding factors (gender, age, CEAP class, Detralex treatment, 
type of procedure), subgroup analyzes will be conducted to determine the effect of these 
variables on expectations and whether there are significant differences for them using the chi-
square test. When analyzing data, a common linear model (the SPSS software feature) will be 
used. 
 
Ethical considerations 
The study will be conducted in accordance with the principles of the Declaration of Helsinki, as 
amended in Fortaleza, Brasil, in 2013. 
Patients will be fully informed, and they will need to provide a written consent before 
participation in the program. The doctor should confirm in the CRF that the patient has 
provided an informed consent. The “Informed consent” also implies individual discussion with 
the patient in their national language about the nature and content of the interview and 
examination to be conducted. 
 
Confidentiality of patient data will be guaranteed by the use of identification (ID) numbers. The 
relation between ID number and patient's identity will be known only to investigators, which 
will ensure the anonymity of patients. 
 
Data collection 
Please inform patients about their participation in this survey using the patient information 
sheet attached to this file. All the CRFs that you completed will be sent to Servier. Data 
anonymity is guaranteed. 
 
Results 
The data you obtained will be used to prepare the study reports under supervision of 
independent scientific experts. 
 
Publications of results 
Before being sent for publication, any manuscript, containing the results of the present study, 
should be provided to Servier company for reviewing. Servier company reserves the right to 
ask for modifications if needed. 
 
 

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APPENDIX 1. 
Adverse event / Adverse drug reaction / Special Situation Reporting Form*  
 
IC4-05682-055-RUS Please send this form immediately by fax (495) 937-47-66 or by email to 
pvmail.rus@servier.com, or pass it to the associate of the company. 
Year of birth   or      Age              Gender 
  Height 
 Weight                       Patient’s ID: 
 
|__|__|__|__|       or   |__|__|__|             M / F 
  |__|__|__| 
  |__|__|__| 
        |_|_|_|_|_|_|_|_|_|_| 
     
Description of adverse event/reaction/special situation: 
Date of event onset 
 
|_|_|  |_|_|  |_|_|_|_| 
Date of event  
termination (in case 
of recovery) 
 
|_|_|  |_|_|  |_|_|_|_| 
 
 
 
Criteria of seriousness:  NO 
 
                        YES (please, specify from stated below)  
 
 Death   
 
 Life threatening 
 
 Hospitalization or prolongation of existing hospitalisation 
 
 Persistent or significant disability or incapacity 
 
 Congenital anomaly/birth defect 
 
    Medically important event 
Outcome: 
 
 Recovered    
 
 Recovered with consequences (persistent  
      structural or functional impairment) 
 
 Not yet recovered   
 
 No recovery 
 
 Death  
 
 Unknown 
General disease(s) / Concomitant disease(s) (please indicate year when first diagnosed). 
Course adverse event/reaction/special situation (please enclose relevant findings, e.g. laboratory, hospital reports, 
histology, etc.): 
 
 
Causal relationship with intake of investigational drug:⁬ 
 
 NO 
          
 YES  
 NOT APPLICABLE 
 
If  «Yes», please indicate dates of the use of investigational drug in the first line of the table below:  
 
If «No» or «Not applicable», please specify whether the adverse event/special situation is related to the medication 
of Servier company (which is specified in the table below): 
  NO         YES 
Please indicate the name of the medication of Servier company: ………………………… 
List of current 
medications  
Daily dose / 
route of 
administration
Dates of intake: 
from 
to 
Indication 
 
 
- 
 
 
 
 
 
 
 
- 
 
 
 
- 
 
 
 
 
 
Name (last, first, patronymic) of doctor:  
Speciality:  
Work address: 
Phone number: ________________________________________ 
                                 (city code) 
Date:                                                         
 
 
Signature: 
*Special situations are cases when adverse event was not observed, but the information should be collected: the impact of the 
drug during pregnancy/breastfeeding, abuse, misuse, medication error, overdose, off-label use, occupational exposure, or 
treatment failure…  
Stamp 
(whenever possible)