VAP-PRO-C6. Effectiveness and Tolerability of Venoactive Drugs in Combination Therapy and Their Effect on the Overall Treatment Outcomes in Patients With Chronic Venous Diseases of CEAP Classes C6 in Real Clinical Practice
Conditions: Chronic Venous Insufficiency
Sponsor: Servier Russia

1 
 
 
 
 
 
 
 
Multicenter observational program VAP-PRO-C6  
  
Protocol N° IC4-05682-066-RUS 
 
 NCT04757766  
 
Effectiveness and tolerability of venoactive drugs in 
combination therapy and their effect on the overall treatment 
outcomes in patients with chronic venous diseases of CEAP 
classes C6 in real clinical practice.  
23\12\2020 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

2 
 
 
Multicenter Observational Program  
VAP-PRO-C6 
Protocol N° IC4-05682-066-RUS 
 
Effectiveness and tolerability of venoactive drugs in combination therapy 
and their effect on the overall treatment outcomes in patients with chronic 
venous diseases of CEAP classes C6 in real clinical practice 
 
Rationale 
Currently, about 40 million people in Russia, mostly of working-age population, suffer from 
various forms of chronic venous diseases (CVDs) [1]. 
Progressive trophic disorders of soft tissues in decompensated forms of CVD contribute to the 
development of long-term non-healing venous ulcers (VUs) and are the most common cause of 
this complication [2, 3]. 
The challenges in the treatment of patients with long-term non-healing VUs related to 
decompensated forms of chronic venous insufficiency (CVI) represent one of the urgent and 
socially significant problems in modern medicine. 
The number of patients with VUs is growing steadily each year by 0.20 - 0.35% [4]. 
A high prevalence of trophic ulcers of venous ethiology and their tendency to recur sunstantiate 
the need for using optimal combination of the most effective modern methods of treatment. 
The local wound care and the use of compression therapy constitute the basis of standard 
treatment of VUs [5]. According to published data, the rate of ulcer healing with this standard 
treatment varies widely and ranges from 45% [6] to 83% [7] after 24 weeks of treatment. 
However, the medical costs associated with the long-term treatment of such chronic wounds are 
substantial [5,8]. These problems in the treatment of VUs have generated interest in the use of 
pharmacotherapy to accelerate their healing. 
To date, there is no consensus on this topic, and a comprehensive staged approach is underused 
in the treatment of patients with VUs in routine clinical practice. All of this became a rationale 
to carry out the present study. 
References 
1. Savelyev V.S., Kirienko A.I., Bogachev V.Yu. Chronic venous diseases in the Russian 
Federation. Results of an international research program VEIN CONSULT. Flebologiya. 2010; 
4 (3): 9-12. [in Russ.] 
2. Savelyev V.S. Phlebology Moscow: 2001 [in Russ.] 
3. Shevchenko Yu.L., Stoyko Yu.M. Fundamentals of Clinical Phlebology. Moscow: ZAO 
“Shiko”, 2013. [in Russ.] 
4. Bogdanets L.I., Plavnik R.G., Smirnova E.S. et al. The efficacy of compression hosiery in the 
prevention of recurrence of trophic ulcers of venous origin. Flebologiya. 2015; 9 (2): 34-42. [in 
Russ.] 
5. Ennis WJ, Meneses P. Standard, appropriate, and advanced care and medical-legal 
considerations: part two-venous ulcerations. Wounds 2003;15:107-122. 
6. Scottish Leg Ulcer Trial Participants. Effect of a national community intervention program on 
healing rates of chronic leg ulcer: randomised controlled trial. Phlebology 2002;17:47-53. 
7. McMullin GM. Improving the treatment of leg ulcers. Med J Aust 2001;175:375-378. 

3 
 
8. Nelzen O, Bergquist D, Lindhagen A. Venous and non-venous leg ulcers: clinical history and 
appearance in a population study. Br J Surg 1994;81:182-187. 
 
Design 
The VAP-PRO-C6 is a Russian multicenter observational program to be implemented at the 
routine visits and assessments. The program will include patients with chronic venous disease of 
CEAP classes C6. This program is planned to be carried out in Russia in 2021-2022. It is expected 
that 90 phlebologists from 60 cities of Russia will take part in the program. The planned number 
of patients is 450. 
 
Program milestones:  
First Patient First Visit 
 
 
Q1\2021 
Last Patient Last Visit  
 
 
Q4\2021 
Completion of statistical analysis 
 
Q1\2022 
Preliminary report 
 
 
 
Q2\2022 
 
Final report 
 
 
 
 
Q2\2022 
 
Aim of the program 
to describe effectiveness and tolerability of systemic pharmacotherapy as a part of combination 
therapy and its effect on the overall treatment outcomes in patients with venous ulcers (CEAP 
classes C6) treated in real clinical settings. 
Primary goal: 
 
1. Description of effectiveness of systemic pharmacotherapy as a part of combination therapy. 
Variables: 
- % of patients with complete healing of the reference
* venous ulcer after 6 months;  
- change in the mean Venous Clinical Severity Score (VCSS) (1); 
- % of patients with reduction in the CVD clinical class by CEAP classification (2). 
 
Secondary goals: 
 
1. Description of additional parameters of the effectiveness of systemic pharmacotherapy as a 
part of combination therapy.  
Variables: 
- time to healing of the reference VU;  
- % of patients with healed reference VU after 3 months of treatment; 
- change in the area of reference VU in cm² (measured with LesionMeter application) (4) 
 
2. Description of changes in the quality of life (QoL) measured by the CIVIQ-14 (3): 
Variables: 
- Global Index Score (GIS) of CIVIQ-14. 
 
3. Description of the adherence to systemic pharmacotherapy as a part of the combination 
therapy in patients with VUs and CVD of CEAP class C6: 
Variables: 
- % of patients who continue to use the prescribed VAD at V1, V3 (interim), and V4 visits (if 
applicable)  
 
* Reference venous ulcer is a primary active venous ulcer, selected by investigator for the follow-up and 
reporting in the Case Report Form (CRF) in case several ulcers are present in the patient. 

4 
 
The reference VU should meet the following criteria:  
• area is no less than 5 cm² but no more than 30 cm²  
• phase 2 or 3 of the wound healing process; 
• location on the medial aspect of lower third of leg. 
 
1) Rutherford RB, Padberg FT Jr, Comerota AJ, Kistner RL, Meissner MH, Moneta GL; 
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.  
2) Lurie F., Passman P., Meisner M. et al. The 2020 update of the CEAP classiﬁcation system 
and reporting standards. // J Vasc Surg: Venous and Lym Dis 2020;8:342-52;  
3). 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. 
4) https://ilyukhin.info/articles/lesionmeter_-_izmerenie_ploshhadi_jazv. Last accessed: July 7, 
2020. 
 
Methods 
Each treating physiciann includes at least 5 patients in the program that meet the inclusion 
criteria. The inclusion period lasts for 6 months. The treatment will be consistent with routine 
clinical practice, local label for the medical use of drugs and the specific clinical situation. The 
following objective methods will be used to assess the changes in the skin condition: 
 
• measurement of the area of reference ulcer (using LesionMeter
†) before and after the 
treatment;  
• changes in status localis. 
 
Duplex ultrasound study (DUS): 
 
• The presence and location of venous reflux and/or occlusion. 
 
Important: Measurement data are recorded for the limb where the reference ulcer is located. 
 
Please note, that DUS will be performed only at the inclusion visit to objectively confirm 
diagnosis of CVD. Once the diagnosis confirmed, further examination with DUS is not 
required without specific indications for reevaluation.  
 
Patient management 
The study does not implicate any intervention to routine management of patients with chronic 
venous disease (CVD). In particular, in this study the parameters that are usually evaluated during 
the examination of patients with classes C6 CVD (CEAP) will be recorded. Special attention will 
be paid to evaluating changes of the area of referent VU using objective methods (measuring 
ulcer area using LesionMeter, time to ulcer healing). 
 
Treatment 
The observational nature of the program implies that all examinations, procedures and changes 
in the treatment of patients, including changes in the dosing regimen, should be carried out only 
on the basis of judgment of the treating physician and in full compliance with the guidelines on 
the treatment of patients with CVD, local labels for medical use of drugs, and in the settings of 
daily routine practice. 
 
† LesionMeter is a generally available tool for measuring the venous ulcer area.   

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Therapy is conducted in full accordance with existing guidelines. The patient’s participation in 
the program, as well as his/her refusal to continue such participation, should not affect the current 
treatment, the availability of diagnostic procedures or the volume and quality of other necessary 
medical care. 
The names and doses of drugs used for the CVD treatment, as well as changes in their doses will 
be recorded in the Case Report Form. 
Inclusion criteria: 
• CVD documented by venous DUS 
▪ Age over 18 years 
▪ Written informed consent is provided 
▪ No treatment with venoactive drugs within 4 weeks prior to inclusion in the study 
▪ Presence of a primary /active venous ulcer (class C6/ CEAP) that meets criteria for the 
referent ulcer 
▪ No surgical intervention or procedure (including sclerotherapy) for CVD is planned  
 
Non-inclusion criteria: 
• Obliterating atherosclerosis 
• Lymphatic edema of the lower extremities 
• Angiodysplasia, neoplasia 
• Peripheral artery disease (ankle-brachial index 0,8-1,3) 
• Infectious process in the previous 6 weeks  
• The presence of one or more comorbidities in the patient that can affect the results: 
✓ Connective tissue diseases (including rheumatoid arthritis, arthritis) 
✓ Chronic heart failure 3-4 function class (NYHA)  
✓ Chronic kidney disease 
✓ Diabetes mellitus experience of at least 10 years and more or Diabetes mellitus 
experience less than 10 years, but decompensated. Diabetic foot. 
✓ Skin diseases of non-venous origin 
✓ Intermittent claudication (peripheral artery disease) 
✓ Diseases of bones or joints of the lower limbs, that can affect the course of the ulcer 
according to the researcher 
✓ Malignant neoplasm 
• Treatment with drugs that can cause edema of the lower extremities (calcium channel 
blockers, hormonal agents, NSAIDs, etc.) 
• History of deep vein thrombosis (within 1 year prior to inclusion) 
• History of superficial venous thrombophlebitis (within 3 months prior to inclusion) 
• The patient underwent surgery for CVD in the previous 3 months  
• Patient cannot walk (regardless of the cause) 
• Poor predicted adherence to treatment 
• Participation in an intervention study in the previous 3 months  
• For women: pregnancy or breastfeeding, or willing to become pregnant within at least 2 
months after the end of the study  
• The necessity, according to the doctor-investigator, of treatment with any diosmin-
containing drug outside of its approved indications (off-label) or in the presence of 
contraindications stated in the instruction for medical use of this drug relevant in the 
Russian Federation at the time of the study, within the scope of this protocol 
• Use of a topical agent that is contraindicated in case of compromised skin integrity  

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Exclusion criteria: 
• Withdrawal of the informed consent 
• Pregnancy or willingness to become pregnant within at least 2 months after the end of the 
study 
• Indications for surgery (including sclerotherapy) 
• Serious violation or non adherence to the prescribed therapy/ regimen   
• Use of prohibited drugs that can cause edema of lower extremities (calcium channel 
blockers, hormonal agents, NSAIDs, etc.) 
 
Treatment effectiveness criteria 
1. Venous Clinical Severity Score (VCSS)  
2. Clinical class of CVD by CEAP classification (2020)  
3. Changes in the parameters of skin condition: 
- area of the reference venous ulcer (measured by LesionMeter) 
- changes in status localis  
- changes in symptoms (pain) as assessed by visual analogue scale (VAS). 
4. The quality of life (QoL) questionnaire CIVIQ-14 (Appendix 2). 
 
Data collection during the study 
At scheduled visits participating physycians will be assessing and collecting parameters of 
interest which they should input in eCRF.  
At the inclusion visit (V0) following data will be collected: a signed consent form, demographic 
characteristics (age, sex, body weight, BMI and height), eligibility of a patient to the inclusion/ 
non inclusion criteria, history and risk factors of CVD, history and current status of taking drugs 
and non drug treatments for CVD; all parameters of VCCS including characteristics of symptoms 
for CVD such as pain, hyperaemia, characteristics of the ulcer(s) etc., characteristics of the 
reference ulcer; results of evaluation of the stage of the disease (CEAP classification); results of 
DUS characterizing venous reflux and its location, presence or absence of venous occlusion and 
its location; skin condition/ pain severity will be patient-reported evaluation with VAS, results 
of a self-assessed quality of life status performed by completing CIVIQ 14 questionnaire; 
assigned treatment for CVD including data on administered  topicals, systematic 
pharmacotherapy, compression therapy.  
At visits 1; 2; 3 (V1; V2;V3) following data will be collected: eligibility of a patient to exclusion 
criteria; characteristics of the ulcer(s) etc., characteristics of the reference ulcer; skin condition/ 
pain severity will be patient-reported evaluation with VAS; any changes in the administered 
treatment for CVD including usage of topicals, usage of systematic pharmacotherapy, usage of 
compression therapy; information regarding any adverse event/ adverse drug reaction or special 
situations (see chapter Safety Considerations).  
At visit 4 (V4) following data will be collected: eligibility of a patient to exclusion criteria; all 
parameters of VCCS including characteristics of symptoms for CVD such as pain, hyperaemia, 
characteristics of the ulcer (s) etc., characteristics of the reference ulcer; results of evaluation of 
the stage of the disease (CEAP classification); skin condition/ pain severity will be patient-
reported evaluation with VAS; results of a self-assessed quality of life status performed by 

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completing CIVIQ 14 questionnaire; any changes in the administered treatment for CVD 
including usage of topicals, usage of systematic pharmacotherapy, usage of compression therapy; 
information regarding any adverse event/ adverse drug reactions or special situations (see chapter 
Safety Considerations). 
 
 
SCHEDULE OF THE STUDY 
 
Actions 
V0 visit 
(inclusion) 
V1 visit  
(1 month 
after V0 visit) 
V2 visit 
(3 months after 
V0 visit)** 
V3 visit 
(interim), if 
applicable* 
V4 visit 
(6  months 
after V0 visit) 
Informed consent 
+ 
 
 
 
 
Inclusion/ Non 
inclusion criteria  
+ 
 
 
 
 
Exclusion criteria  
 
+ 
+ 
+ 
+ 
Reporting of AEs 
 
+ 
+ 
+ 
+ 
Completion of the CRF  
+ 
+ 
+ 
+ 
+ 
VCSS  
+ 
 
 
 
+ 
CEAP clinical class 
+ 
 
 
 
+ 
Skin changes (by VAS) 
+ 
+ 
+ 
+ 
+ 
Status localis 
+ 
+ 
+ 
+ 
+ 
DUS (presence of 
reflux) 
+ 
 
 
 
 
QoL assessment 
(CIVIQ-14) 
+ 
 
 
 
+ 
Data on the treatment 
and its change 
 
+ 
 
+ 
 
+ 
 
+ 
 
+ 
Venoactive drug  
+ 
+ 
+ 
+ 
+ 
Compression hosiery  
+ 
+ 
+ 
+ 
+ 
Topical treatment 
+ 
+ 
+ 
+ 
+ 
* The visit takes place if the venous ulcer is healed between V2 and V4 visits 
**The visit can be replaced by telephone interview which remains at discretion of the doctor-
investigator 
 
 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); 
- suspected  transmission  of  an infectious agent via  a  medicinal  product;  
- unexpected beneficial action of the drug; 
- lack of the treatment efficiency of drug. 
1.2. Adverse Event (AE)  

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Adverse event is any untoward medical occurrence in a patient or a clinical-trial subject 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 related to the medicinal product. 
1.3. Adverse (drug) reaction (ADR)  
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 reported events occurring during the study will be 
recorded:   
- 
All serious adverse drug reactions related to any Servier drug and/or to other venoactive 
drugs   
- 
All non-serious adverse drug reactions related to any Serveier drug and/or to other 
venoactive drugs    
- 
All reports about special situations (see 1.1) 
- 
All adverse events 
 
2.2. Responsibilities of the treating physician   

9 
 
In prospective studies, at medical visits, the treating physician will ask the patient participating 
in the study to indicate whether or not an adverse event (serious or not) has occurred. 
The treating physician has to assess the causal relationship between an adverse event and a 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 treating physician 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.  
When assessing the quality of life using the EQ-5D, the treating physician should evaluate data 
(patient's answers), their clinical relevance, and fill out the " Adverse event / Adverse drug 
reaction / Special Situation Reporting Form” if he/she considers these data as AE, ADR or a 
special situation.  
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.ru@servier.com or by fax to 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 a treating physician within 2 working days. 
In case there is an ADR related to a non-Servier venoactive drug, the treating physician must 
report the pharmacovigilance data to the appropriate authorities in accordance with the Good 
Vigilance Practice and local regulations  
The same rules apply for the transferring of additional information about the event.  
The treating physician must ensure the appropriate follow-up of the patient depending on the 
nature of event, until it resolves. The treating physician will continue to notify follow up data 
according to timeframes defined above. 
If a treating physician does not follow-up a patient 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 the Sponsor/Marketing Authorization Holder 
Independently of the regulatory obligations of the treating physician, 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 stabilised and 
the report is deemed sufficiently detailed for adequate medical analysis of the case. 
 
Statistical parameters 
Statistical analysis: 
The baseline characteristics will be analyzed in all included patients regardless of the patient's 
adherence to the protocol procedures (intention-to-treat analysis). The analysis of the study 
results will be carried out using the SPSS 12.0 software package (SPSS Inc., USA). Data entry 
errors will be corrected before the start of statistical processing. Quantitative parameters will be 
presented taking into account the distribution of raw data, in the form of arithmetic mean ± 
standard deviation for parametric, and in the form of a median (25; 75 percentile) for 
nonparametric variables. Accordingly, a comparison on quantitative parameters between the 

10 
 
groups with different adherence will be carried out using the Student's t-test for independent 
samples or using the Mann-Whitney U-test. 
For multiple comparisons, a correction for continuity will be implemented. The changes in 
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. 
Changes in the quantitative parameters, both in the independent groups and during the follow-up 
period, will be evaluated as the difference between the mean values and the corresponding 95% 
confidence intervals. 
Differences between the groups by the mean score of the VAS, VCSS, and CIVIC-14, and by an 
integrated index of skin changes (lesion area, ultrasound data) will be carried out using two-way 
analysis of variance with repeated measures, in order to compare scores before and after the 
treatment. 
Safety will be assessed in all patients who received at least one dose of any venoactive drug 
during the study (studied drugs). 
Adverse events will be recorded and analyzed in patients, and all adverse events, serious adverse 
events, adverse reactions, serious adverse reactions and special situations will be listed. 
 
Ethical considerations: 
The study will be conducted in accordance with the principles set out in the Declaration of 
Helsinki (version adopted in Fortaleza, Brazil, in 2013). 
Participants will be fully informed about the program and provide their written consent to 
participate in it. Treating physician is obliged to indicate in the CRF that the informed consent 
has been obtained from the patient. The “informed consent” also means that individual discussion 
with a participant concerning nature of the program and necessity of examinations and 
evaluations used in the study took place.  
The confidentiality of patient data will be guaranteed using identification code numbers (IDs). 
The relation between the ID and the patient identity will be known only to a treating physician, 
so that will ensure the anonymity of patient’s data. 
Data collection: 
Treating physician will inform patients about their participation in this program using the Patient 
Information form (attached to this file). All CRFs filled by a treating physician will be sent to 
Servier. Data anonymity is guaranteed. 
Results: 
The obtained data will be used to generate a study report under the supervision of independent 
scientific experts. 
 
Publication of the results: 
Any manuscript containing the results of this study must be submitted to Servier for review 
before submission to publication. Servier reserves the right to ask for modifications, if necessary. 
 
 
 
 

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Appendix 1. 
 
Adverse event / Adverse drug reaction / Special Situation Form*  
 
IC4-05682-066-RUS Please send this form immediately by fax (495) 937-47-66 or by email to 
pvmail.ru@servier.com, or pass 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 significant 
Outcome: 
 
 Recovered    
 
 Recovered with sequelae 
 
 Recovering   
 
 Not recovered 
 
 Fatal 
 
 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 the studied drug intake**: 
 
 NO 
          
 YES  
 NOT APPLICABLE 
 
If yes, please specify dates of treatment with the studied drug in the table below on the first line:  
 
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, treatment 
failure, suspected  transmission  of  infectious  agents  via  a  medicinal  product, or unexpected beneficial action of the drug. 
Stamp 
(whenever possible) 

12 
 
**  the studied drug is defined  in the Safety Consideration section of the protocol. 
 
Appendix 2. 
 
 
 
 
 
 

13 
 
 

14 
 
 
 
 

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