Comparative Assessment of the Efficacy and Safety of Venoactive Drug Treatment of Pelvic Venous Disorders
Phase: PHASE3
Conditions: Pelvic Venous Disorders
Sponsor: Pirogov Russian National Research Medical University

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Study protocol: «Comparative assessment of the efficacy and safety of 
venoactive drug treatment of pelvic venous disorders: results of a single-
center randomized open trial» 
ID: NCT06584799 
Date: 09/04/2024 
 
 
Project Summary 
Venoactive drug (VAD) therapy is one of the most effective methods of treating chronic venous 
diseases (CVD) [1-3]. Numerous studies have proven its high efficacy in relieving symptoms of 
CVD, such as leg pain and swelling, leg heaviness and fatigue, as well as an association between 
the VAD intake and acceleration of venous ulcer healing [4-8]. Pelvic venous disorders (PeVDs) 
represent a group of pathological conditions including varicose veins of the pelvis and vulva, and 
compression stenoses of the left renal and common iliac veins. Although PeVDs are associated 
with venous lesions of the pelvis and retroperitoneum and have specific clinical manifestations, 
they are one of the forms of CVD and constitute a separate cohort [9,10]. A number of studies on 
the VAD usage in PeVD indicate the wide possibilities of this type of treatment in eliminating 
chronic pelvic pain (CPP), the most dramatic symptom of PeVD, which is the main cause of 
disability and decreased quality of life, social and daily activity in women with PeVD. The 
healthcare systems of industrialized countries are known to spend annually more than 2 billion US 
dollars on the treatment of patients with PeVD and CPP, and the cost of treating one patient with 
PeVD ranges from 3,600 to 27,000 US dollars per year [11-13]. 
Currently, a variety of VADs are presented on the pharmaceutical market, which, according to the 
product labels, provide effects not only on the venous outflow from the lower extremities, but also 
on venous hemodynamics in the pelvis [14]. At the same time, a literature analysis shows that 
micronized purified flavonoid fraction (MPFF, Detralex, Daflon) has the greatest evidence base 
obtained in the efficacy and safety studies of VADs in PeVD [15-19]. Nevertheless, patients are 
rarely interested in the scientific dossier of drugs, and in the real practice the patients with PeVD 
and CPP most often ask: “What is the best drug to use for the CPP relief?” This is quite 
understandable, as it is CPP in PeVD that results not only in disability, but also in family conflicts, 
psycho-emotional stress and depressive states [20,21]. In this regard, patients seek to get rid of 
pain as soon as possible and strive to use the most effective drug.  
An extensive scientific base of comparative studies on the use of various VADs in patients with 
CVD and PeVD has been accumulated to date [15-19, 22-26]. However, the literature is lack of 
any data on the comparative efficacy and safety of VADs in the treatment of patients with PeVD. 

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This, in turn, makes not possible for doctors and patients to choose the optimal and most effective 
drug based on the objective research data. All the above has predetermined the purpose of the 
planned study as evaluating the efficacy and safety of different VADs in the treatment of female 
patients with PeVD. 
References 
1. Martinez-Zapata MJ, Vernooij RWM, Simancas-Racines D, Uriona Tuma SM, Stein AT, 
Moreno Carriles RMM, et al. Phlebotonics for venous insufficiency. Cochrane Database 
of 
Systematic 
Reviews 
2020, 
Issue 
11. 
Art. 
No.: 
CD003229. 
https://doi.org/10.1002/14651858.cd003229.pub4  
2. De Maeseneer MG, Kakkos SK, Aherne T, et al. Editor's Choice - European Society for 
Vascular Surgery (ESVS) 2022 Clinical Practice Guidelines on the Management of 
Chronic Venous Disease of the Lower Limbs. Eur J Vasc Endovasc Surg. 2022;63(2):184-
267. https://doi.org/10.1016/j.ejvs.2021.12.024  
3. Gloviczki P, Lawrence PF, Wasan SM, et al. The 2023 Society for Vascular Surgery, 
American Venous Forum, and American Vein and Lymphatic Society clinical practice 
guidelines for the management of varicose veins of the lower extremities. Part II: Endorsed 
by the Society of Interventional Radiology and the Society for Vascular Medicine. J Vasc 
Surg 
Venous 
Lymphat 
Disord. 
2024;12(1):101670. 
https://doi.org/10.1016/j.jvsv.2023.08.011  
4. Management of chronic venous disorders of the lower limbs. Guidelines according to 
scientific evidence. International Angiology. 2007;26:1-59. https://doi.org/10.1007/978-
81-322-1991-0_11 
5. Nicolaides A, Kakkos S, Baekgaard N, Comerota A, de Maesenner M, Eklof B, et al. 
Management of chronic venous disorders of the lower limbs. Guidelines according to 
scientific 
evidence. 
Part 
I. 
Int 
Angiol. 
2018;37(3):181–254. 
https://doi.org/10.23736/s0392-9590.18.03999-8  
6. Nicolaides A, Kakkos S, Baekgaard N, Comerota A, de Maeseneer M, Eklof B. 
Management of chronic venous disorders of the lower limbs. Guidelines According to 
Scientific 
Evidence. 
Part 
II. 
Int 
Angiol. 
2020;39(3):175-240. 
https://doi.org/10.23736/s0392-9590.20.04388-6  
7. Rabe E, Blanc-Guillemaud V, Onselaer MB, Blangero Y, Yaltirik HP, Nicolaides A. 
Reduction of lower-limb edema in patients with chronic venous disease by micronized 
purified flavonoid fraction: a systematic literature review and meta-analysis. Int Angiol. 
2023;42(6):488-502. https://doi.org/10.23736/s0392-9590.23.05084-8 

3 
 
8. Ulloa JH, Lurie F, Santiago FR, et al. Systematic literature review and expert meeting 
report on health-related quality of life in chronic venous disease. Int Angiol. 
2023;42(6):465-476. https://doi.org/10.23736/s0392-9590.23.05108-8 
9. Antignani PL, Lazarashvili Z, Monedero JL, et al. Diagnosis and treatment of pelvic 
congestion syndrome: UIP consensus document. Int Angiol. 2019;38(4):265-283. 
https://doi.org/10.23736/s0392-9590.19.04237-8 
10. Meissner MH, Khilnani NM, Labropoulos N, et al. The Symptoms-Varices-
Pathophysiology classification of pelvic venous disorders: A report of the American Vein 
& Lymphatic Society International Working Group on Pelvic Venous Disorders. J Vasc 
Surg 
Venous 
Lymphat 
Disord. 
2021;9(3):568-584. 
https://doi.org/10.1016/j.jvsv.2020.12.084 
11. Rognoni C, Lugli M, Maleti O, Tarricone R. Venous stenting for patients with outflow 
obstruction and leg ulcers: cost-effectiveness and budget impact analyses. J Comp Eff Res. 
2020;9(10):705-720. https://doi.org/10.2217/cer-2020-0030  
12. Tangney E, O’Donnell T, Iafrati M. Cost and Benefit Analysis of Stenting Versus 
Compression Therapy for Patients With Chronic Total Venous Occlusion. J Vasc Surg 
Venous Lymphat Disord. 2016;4(1):137. https://doi.org/10.1016/j.jvsv.2015.10.014 
13. Huang G, Le AL, Goddard Y, James D, Thavorn K, Payne M,, et al. A Systematic Review 
of the Cost of Chronic Pelvic Pain in Women. J Obstet Gynaecol Can. 2022;44:286-93. 
https://doi.org/10.1016/j.jogc.2021.08.011 
14. 14. Vidal-2023. Vidal Manual. Medicines in Russia. 2023. – Moscow. – Vidal Rus. 1160 
pp. [in Russian] 
15. Rabe E, Guex JJ, Morrison N, et al. Treatment of chronic venous disease with flavonoids: 
recommendations for treatment and further studies. Phlebology. 2013;28(6):308-319. 
https://doi.org/10.1177/0268355512471929 
16. Bush R, Comerota A, Meissner M, Raffetto JD, Hahn SR, Freeman K. Recommendations 
for the medical management of chronic venous disease: The role of Micronized Purified 
Flavanoid Fraction (MPFF) [published correction appears in Phlebology. 2017 Dec;32(10 
):NP36]. Phlebology. 2017;32(1_suppl):3-19. https://doi.org/10.1177/0268355517692221 
17. Kakkos SK, Nicolaides AN. Efficacy of micronized purified flavonoid fraction (Daflon®) 
on improving individual symptoms, signs and quality of life in patients with chronic venous 
disease: a systematic review and meta-analysis of randomized double-blind placebo-
controlled trials. Int Angiol. 2018;37(2):143-154. https://doi.org/10.23736/s0392-
9590.18.03975-5 

4 
 
18. Gianesini S, De Luca L, Feodor T, Taha W, Bozkurt K, Lurie F. Cardiovascular Insights 
for the Appropriate Management of Chronic Venous Disease: A Narrative Review of 
Implications for the Use of Venoactive Drugs. Adv Ther. 2023;40(12):5137-5154. 
https://doi.org/10.1007/s12325-023-02657-0 
19. Mezalek ZT, Feodor T, Chernukha L, et al. VEIN STEP: A Prospective, Observational, 
International Study to Assess Effectiveness of Conservative Treatments in Chronic Venous 
Disease [published correction appears in Adv Ther. 2023 Nov 23;:] [published correction 
appears in Adv Ther. 2024 Apr 29;:]. Adv Ther. 2023;40(11):5016-5036. 
https://doi.org/10.1007/s12325-023-02643-6 
20. Latthe P, Latthe M, Say L, Gülmezoglu M, Khan KS. WHO systematic review of 
prevalence of chronic pelvic pain: a neglected reproductive health morbidity. BMC Public 
Health. 2006;6:177. https://doi.org/10.1186/1471-2458-6-177 
21. Champaneria R, Shah L, Moss J, et al. The relationship between pelvic vein incompetence 
and chronic pelvic pain in women: systematic reviews of diagnosis and treatment 
effectiveness. Health Technol Assess. 2016;20(5):1-108. https://doi.org/10.3310/hta20050 
22. Simsek M, Burak F, Taskin O. Effects of micronized purified flavonoid fraction (Daflon) 
on pelvic pain in women with laparoscopically diagnosed pelvic congestion syndrome: a 
randomized crossover trial. Clin Exp Obstet Gynecol. 2007;34(2):96-98. 
23. Akhmetzianov RV, Bredikhin RA. Clinical efficacy of Detralex in treatment of women 
with pelvic varicose veins. Angiol Sosud Khir. 2018;24(2):93-99. 
24. Gavrilov SG, Moskalenko YP, Karalkin AV. Effectiveness and safety of micronized 
purified flavonoid fraction for the treatment of concomitant varicose veins of the pelvis 
and 
lower 
extremities. 
Curr 
Med 
Res 
Opin. 
2019;35(6):1019-1026. 
https://doi.org/10.1080/03007995.2018.1552043 
25. Gavrilov SG, Karalkin AV, Moskalenko YP, Grishenkova AS. Efficacy of two micronized 
purified flavonoid fraction dosing regimens in the pelvic venous pain relief. Int Angiol. 
2021;40(3):180-186. https://doi.org/10.23736/s0392-9590.21.04579-x 
26. Akhmetzianov RV, Bredikhin RA. Clinical Efficacy of Conservative Treatment with 
Micronized Purified Flavonoid Fraction in Female Patients with Pelvic Congestion 
Syndrome. Pain Ther. 2021;10(2):1567-1578. https://doi.org/10.1007/s40122-021-00312-
6  
 
 
 
 

5 
 
Study objectives:  
• To evaluate the efficacy of diosmin-containing VADs in the CPP relief in female patients with 
PeVD; 
• To evaluate the safety (by the number of side effects and adverse events) of diosmin-
containing VADs in female patients with PeVD; 
• To compare the efficacy and safety of treatment with different diosmin-containing VADs; 
• To evaluate the patients’ adherence to the different recommended diosmin-containing VADs 
in female patients with PeVD. 
 
Patients and methods: A total of 150 female patients of reproductive age with symptomatic PeVD 
and without any other diseases accompanied by CPP are planned for the inclusion in the study. 
Clinical study: All patients will be examined by an investigating physician. Complaints, medical 
history, and physical examination results will be recorded in the individual patient’s case report 
form (CRF). The severity of CPP will be assessed using a 10-score visual analogue scale (VAS) 
before treatment and then weekly for 2 months of treatment with VAD. 
Diagnostic methods: 
All patients will undergo transabdominal and transvaginal duplex ultrasound scanning (DUS) of 
the pelvic veins. 
Treatment methods: the following VADs will be used as the study drugs. 
1. Micronized purified flavonoid fraction 1000. Manufacturer: SERVIER RUS, LLC 
(Russia). Active substance: micronized purified flavonoid fraction (diosmin+flavonoids 
expressed as hesperidin).  
Micronized purified flavonoid fraction (MPFF) is a venotonic agent that also has 
angioprotective properties. It reduces venous distensibility and blood stasis, capillary 
permeability, and increases capillary resistance. The results of clinical studies confirm the 
pharmacological activity of drugs containing this active substance in relation to the 
parameters of venous hemodynamics. MPFF improves venous tone: a reduction in venous 
emptying time has been shown by venous occlusion plethysmography. In patients with 
signs of severe microcirculatory disorders the treatment with drugs containing this active 
substance is associated with a statistically significant (as compared to placebo) 
improvement in the capillary resistance, as has been shown by angiostereometry. The drug 
also has a proven efficacy in the treatment of CVD of the lower extremities (Source: 
https://www.vidal.ru/drugs/detralex__38634; accessed: September 4, 2023). 
MPFF 1000 dosing regimen is 1000 mg once daily for 2 months. 

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2. Diosmin 600. Manufacturer: INNOTHERA CHOUZY (France). Active substance: 
diosmin.  
Venotonic action: the drug reduces venous distensibility, increases venous tone, reduces 
blood stasis, and enhances the vasoconstrictor effect of epinephrine and norepinephrine. 
The optimal daily dose of diosmin for obtaining venotonic effect is 600 mg.  
Angioprotective action: the drug improves microcirculation, increases capillary resistance, 
and reduces capillary permeability. Effect on the lymphatic system: the drug improves 
lymphatic drainage, increases the tone and frequency of contraction of lymphatic 
capillaries, increases their functional density, and reduces lymphatic pressure. It has an 
anti-edematous effect, reduces symptoms of inflammation (dose-dependent effect), 
reduces adhesion of leukocytes to the venous wall and their migration into paravasal 
tissues, and improves oxygen diffusion and perfusion in tissues. The drug hinders the 
production of free radicals and synthesis of prostaglandins and thromboxane. A double-
blind, placebo-controlled study using Duplex ultrasound has confirmed that the drug 
reduces the mean venous pressure in the system of superficial and deep veins of the lower 
extremities 
(Source: 
https://www.vidal.ru/drugs/phlebodia_600__4622; 
accessed: 
September 4, 2023).  
Diosmin 600 dosing regimen is 600 mg once daily for 2 months. 
3. Hesperidin + Diosmin 1000. Manufacturer: ALLIUM (Russia). Active substance: diosmin 
and hesperidin. 
A venotonic agent that also has angioprotective properties. It reduces venous distensibility 
and blood stasis, reduces capillary permeability and increases their resistance. The results 
of clinical studies confirm the pharmacological activity of drugs containing this active 
substance in relation to the parameters of venous hemodynamics. It increases venous tone: 
a reduction in the time of venous emptying has been demonstrated in studies with venous 
occlusion plethysmography. In patients with signs of severe microcirculatory disorders the 
treatment with drugs containing this active substance is associated with a statistically 
significant (as compared to placebo) improvement in the capillary resistance, which has 
been proven by angiostereometry. The drug has a proven efficacy in the treatment of CVD 
of the lower extremities (Source: https://www.vidal.ru/drugs/gesperidin-diosmin; accessed: 
September 4, 2023).  
Hesperidin + Diosmin 1000 dosing regimen is 1000 mg once daily for 2 months. 
All three of these drugs are venotonic and venoprotective drugs used in the CVD treatment. They 
are comparable in their pharmacological properties, product labels, profile of side effects and 
adverse events, and the cost per package of 30 tablets, according to the Moscow chain of 

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pharmacies 
(Source: 
https://gorzdrav.org/p/detraleks-tabl-p-o-1000mg-n30-62440/; 
https://gorzdrav.org/p/flebodia-600-tabl-p-o-600mg-n30-17602/; https://gorzdrav.org/p/venarus-
tabl-p-o-900mg-100mg-n30-64844/; accessed: September 4, 2023). 
Patients will take these VADs at the same time every morning, during breakfast. Patients will be 
warned in advance about possible side effects and adverse events. In a case of their occurrence, 
the patients shall immediately notify the principal investigator or investigators using one or more 
mobile phone numbers provided to them in advance. 
 
General information 
Study title: «Comparative assessment of the efficacy and safety of venoactive drug treatment of 
pelvic venous disorder: results of a single-center prospective randomized trial» 
Protocol ID: NCT06584799. 
Protocol of the study: The study was approved by the local ethical committee of the Pirogov 
Russian National Research Medical University (Protocol No. 20452024) 
Responsible for the study: Gavrilov Sergey Gennadievich, Doctor of Medical Sciences, Professor, 
Pirogov Russian National Research Medical University, 1Ostrovityanova str., Moscow 117997; 
phone: 8 (495) 434-30-83. 
Department: University Surgical Clinic named after V.S. Savelyev, Room 0076, 10/5 Leninsky 
prospect, Moscow 119049. 
 
Rationale 
Pelvic varicose veins with blood reflux, described as “Pelvic varicose disease” (PVD) or “Pelvic 
venous insufficiency” (PVI), represent one of the nosological entities of PeVD [1]. PVD and PVI 
develop in about 15% of women of reproductive age and 30% of female patients seeking medical 
help for CPP [2,3]. Two third of patients with PVI have no indications for surgical or endovascular 
interventions and require only medical treatment, which is based on VAD. The purpose of VAD 
treatment is to relieve PVI symptoms, primarily CPP, improve venous outflow from the pelvic 
organs, and reduce venous stasis in the pelvis [4,5]. A variety of diosmin-containing VADs are 
successfully used nowadays in the treatment of CVD, including PVI. Many studies have proven 
that their use is associated with the reduction or relief of leg pain, heaviness and swelling, as well 
as a faster healing of the venous ulcers [6,7]. Moreover, a number of studies have demonstrated a 
high efficacy of MPFF in relieving PVI symptoms and pelvic pain [8-12]. CPP significantly 
reduces the quality of life of patients with PVI, their social and household activity, and it is quite 
natural that patients seek to get rid of this suffering as soon as possible, using the most effective 

8 
 
drug in this regard. One of the most frequently asked questions by patients with PVI is: “What 
venoactive drug is best to take in order to relief or alleviate CPP?” 
This is an absolutely natural question, because today the pharmacy chain offers a wide range of 
VADs. Based on an analysis of literature data, the most often used diosmin-containing VADs are 
MPFF (micronized purified flavonoid fraction), Diosmin 600, and the combination of hesperidin 
and diosmin. In the product labels for these VADs, the manufacturers claim about almost identical 
therapeutic effects in relation to the CVD treatment, and advertising campaigns in the media assure 
patients that each of them will provide an excellent effect in the treatment of venous diseases. 
However, there are no studies in the available medical literature comparing the efficacy and safety 
of various VADs in the treatment of PeVD. Moreover, the vast majority of studies on the treatment 
with VADs for PeVD were performed using MPFF 1000 [8-11]. This, in turn, creates the 
impression that the authors of these studies are biased by the manufacturer, i.e. have a conflict of 
interest that promotes the choice of MPFF 1000 for the treatment of PeVD. 
 
References 
1. Meissner MH, Khilnani NM, Labropoulos N, et al. The Symptoms-Varices-
Pathophysiology classification of pelvic venous disorders: A report of the American Vein 
& Lymphatic Society International Working Group on Pelvic Venous Disorders. J Vasc 
Surg 
Venous 
Lymphat 
Disord. 
2021;9(3):568-584. 
https://doi.org/10.1016/j.jvsv.2020.12.084 
2. Belenky A, Bartal G, Atar E, Cohen M, Bachar GN. Ovarian varices in healthy female 
kidney donors: incidence, morbidity, and clinical outcome. AJR Am J Roentgenol. 
2002;179(3):625-627. https://doi.org/10.2214/ajr.179.3.1790625 
3. Ignacio EA, Dua R, Sarin S, et al. Pelvic congestion syndrome: diagnosis and treatment. 
Semin Intervent Radiol. 2008;25(4):361-368. https://doi.org/10.1055/s-0028-1102998 
4. Gavrilov SG, Moskalenko YP, Karalkin AV. Effectiveness and safety of micronized 
purified flavonoid fraction for the treatment of concomitant varicose veins of the pelvis 
and 
lower 
extremities. 
Curr 
Med 
Res 
Opin. 
2019;35(6):1019-1026. 
https://doi.org/10.1080/03007995.2018.1552043  
5. Gavrilov SG, Karalkin AV, Moskalenko YP, Grishenkova AS. Efficacy of two micronized 
purified flavonoid fraction dosing regimens in the pelvic venous pain relief. Int Angiol. 
2021;40(3):180-186. https://doi.org/10.23736/s0392-9590.21.04579-x  
6. Kakkos SK, Nicolaides AN. Efficacy of micronized purified flavonoid fraction (Daflon®) 
on improving individual symptoms, signs and quality of life in patients with chronic venous 
disease: a systematic review and meta-analysis of randomized double-blind placebo-

9 
 
controlled trials. Int Angiol. 2018;37(2):143-154. https://doi.org/10.23736/s0392-
9590.18.03975-5  
7. Gianesini S, De Luca L, Feodor T, Taha W, Bozkurt K, Lurie F. Cardiovascular Insights 
for the Appropriate Management of Chronic Venous Disease: A Narrative Review of 
Implications for the Use of Venoactive Drugs. Adv Ther. 2023;40(12):5137-5154. 
https://doi.org/10.1007/s12325-023-02657-0  
8. Simsek M, Burak F, Taskin O. Effects of micronized purified flavonoid fraction (Daflon) 
on pelvic pain in women with laparoscopically diagnosed pelvic congestion syndrome: a 
randomized crossover trial. Clin Exp Obstet Gynecol. 2007;34(2):96-98 
9. Taskin O., Sahin L., Gavrilov S.G., Lazarashvili Z. Medical treatment of pelvic congestion 
syndrome. Phlebolymphology. 2016;23 (3):146-153. 
10. Akhmetzianov RV, Bredikhin RA. Clinical Efficacy of Conservative Treatment with 
Micronized Purified Flavonoid Fraction in Female Patients with Pelvic Congestion 
Syndrome. Pain Ther. 2021;10(2):1567-1578. https://doi.org/10.1007/s40122-021-00312-
6  
11. Gavrilov SG, Turischeva OO. Conservative treatment of pelvic congestion syndrome: 
indications 
and 
opportunities. 
Curr 
Med 
Res 
Opin. 
2017;33(6):1099-1103. 
https://doi.org/10.1080/03007995.2017.1302414 
12. Gavrilov SG. Vulvar varicosities: diagnosis, treatment, and prevention. Int J Womens 
Health. 2017;9:463-475. https://doi.org/10.2147/ijwh.s126165 
 
Aim and objectives of the study 
Study aim: to evaluate the efficacy and safety of using various diosmin-containing VADs in the 
treatment of patients with PeVD. 
Study objectives:  
1. To evaluate the efficacy of MPFF 1000 in relieving CPP in female patients with PeVD; 
2. To evaluate the efficacy of Diosmin 600 in relieving CPP in female patients with PeVD; 
3. To evaluate the efficacy of Hesperidin + Diosmin 1000 in relieving CPP in female patients 
with PeVD; 
4. To evaluate the safety (the number of side effects and adverse events) of MPFF 1000, Diosmin 
600 and Hesperidin + Diosmin 1000 in the treatment of female patients with PeVD; 
5. To compare the efficacy of MPFF 1000, Diosmin 600 and Hesperidin + Diosmin 1000 relieving 
CPP in female patients with PeVD; 
6. To evaluate the patients’ adherence to the recommended treatment with VADs using MPFF 
1000, Diosmin 600 and Hesperidin + Diosmin 1000 in female patients with PeVD. 

10 
 
Study design 
This will be a single-center randomized study. The period of the study will be from 2023 to 2024. 
The study will include 150 female patients with symptomatic PeVD. 
 
Inclusion criteria:  
• Age from 18 to 45 years; 
• The presence of PeVD symptoms (CPP, dyspareunia, discomfort in the hypogastrium, dysuria, 
vulvar varicose veins); 
• The presence of pelvic varicose veins with reflux in them, according to DUS; 
• Pelvic venous reflux (PVR) lasting for greater than 1 s, according to DUS; 
• Isolated dilation and reflux in the parametrial and uterine veins, according to DUS; 
• Absence of competing abnormalities, accompanied by CPP. 
Exclusion criteria: 
• Asymptomatic form of the disease; 
• Menopause; 
• Pregnancy; 
• Post-thrombotic disease; 
• Neoplasms; 
• Competing diseases with CPP; 
• Known hypersensitivity to any of the components of the used VAD. 
Each patient will sign a voluntary informed consent prior to the inclusion in the study. 
 
Methodology 
The study will include 150 consecutive female patients with symptomatic PeVD, according to the 
inclusion/exclusion criteria. All patients will undergo a clinical examination, transabdominal and 
transvaginal DUS of the pelvic veins to verify the diagnosis and to determine the diameters of the 
pelvic veins and the duration of reflux in them. The study will include patients with PeVD and 
isolated dilation and reflux in the parametrial and uterine veins. Previous studies have shown that 
the use of VADs in patients with a combination of reflux in the ovarian, parametrial and uterine 
veins is ineffective [4,14]. The CPP intensity will be assessed using a visual analogue scale (VAS), 
which is a 10-cm horizontal line ranged from 0 to 10 scores (1 cm equals 1 score). The CPP 
intensity will be assessed by VAS scores as following: 0, no pain; 1-3, mild pain; 4-6, moderate 
pain; 7-10, severe pain. After a brief instruction by an investigator, the patients will rate their pain 
intensity by making a mark on the line.  

11 
 
For randomization procedure, the sealed envelope principle will be used. Three groups of 50 
patients each will be formed depending on the recommended VAD usage: group 1 (n=50) with 
MPFF1000; group 2 (n=50) with Diosmin 600; and group 3 (n=50) with Hesperidin + Diosmin 
1000. After the start of VAD intake, the patients will be self-rating the pain intensity on VAS on 
the weekly basis. After 60 days from the VAD treatment start, the patients will undergo repeated 
clinical examination and provide an investigator with 8 completed VAS forms. Based on the 
repeated examination data and the VAS results, a comparative analysis of the clinical efficacy of 
VADs will be carried out. In a case of side effect or adverse event occurrence during a 2-month 
treatment course, patients inform the doctor-investigator about it within one day, and the decision 
is made either to continue, change the regimen of treatment or to discontinue it. Flow chart of the 
study is presented in Figure 1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Figure 1. Flow chart of the study. Abbreviations: PeVD, pelvic venous disease; DUS, duplex 
ultrasound scanning; OVs, ovarian veins; PVs, parametrial veins; UVs, uterine veins; CPP, chronic 
pelvic pain. 
 
1. 
Clinical examination includes obtaining medical history and information about complaints, 
physical examination, assessment of the local vascular status and measurement of the pain 
intensity by VAS. The clinical examination is carried out before DUS of the pelvic veins 
and then is repeated after completion of the VAD treatment course (i.e. after 2 months). 
2. Transabdominal and transvaginal DUS of the pelvic veins is carried out after clinical 
examination and includes assessment of the patency and diameters of the pelvic veins, iliac 
Female patient with a suspected PeVD 
Clinical examination, DUS of pelvic 
veins; consultations of allied specialists 
Patients with symptomatic PeVD 
(n=150) 
Randomization 
MPFF 1000 
(n=50) 
Diosmin 600 
(n=50) 
Hesperidin + Diosmin 
1000 (n=50) 
Comparative assessment  
of the treatment results 
• Asymptomatic form of PeVD; 
• Combination of dilation and 
reflux in OVs, PVs or UVs; 
• Menopause; 
• Pregnancy; 
• Post-thrombotic disease; 
• Neoplasms; 
• Competing diseases with CPP; 
• Known hypersensitivity to any 
of the VAD components 

12 
 
veins, inferior vena cava and renal veins, as well as identification of the blood reflux 
through the pelvic veins (gonadal, parametrial, uterine veins). Separately, the status of the 
left renal vein (LRV) is evaluated based on the measurements of its diameter and blood 
flow velocities in the area of intersection with the superior mesenteric artery and in the 
region of the renal hilum, as well as by calculating the diameter ratios and velocity ratios 
to assess the degree of LRV stenosis.  
3. Venoactive drug treatment. Diosmin-containing VADs (MPFF 1000, Diosmin 600, 
Hesperidin + Diosmin 1000) will be used in accordance with the treatment regimens stated 
above. 
The data of clinical examinations and DUS will be recorded in the patient’s individual CRF. 
 
References 
1. Gavrilov SG, Moskalenko YP. Does pelvic congestion syndrome influence symptoms of 
chronic venous disease of the lower extremities? Eur J Obstet Gynecol Reprod Biol. 
2019;243:83-86. https://doi.org/10.1016/j.ejogrb.2019.10.025  
2. Gavrilov SG, Moskalenko YP, Efremova OI. Does the dilation of pelvic veins affect the 
symptoms of chronic venous disease in patients with combined varicose veins of the pelvis 
and lower extremities? Flebologiya. 2019;13(2):112-118 [in Russian]. 
3. Gavrilov SG, Moskalenko YP, Efremova OI. Pelvic venous congestion aggravates the 
symptoms of chronic venous insufficiency. RMJ. 2018;26(6-2):65-69 [in Russian]. 
4. Gavrilov SG, Moskalenko YP, Karalkin AV. Effectiveness and safety of micronized 
purified flavonoid fraction for the treatment of concomitant varicose veins of the pelvis 
and 
lower 
extremities. 
Curr 
Med 
Res 
Opin. 
2019;35(6):1019-1026. 
https://doi.org/10.1080/03007995.2018.1552043  
5. Gavrilov SG, Karalkin AV, Moskalenko YP, Grishenkova AS. Efficacy of two micronized 
purified flavonoid fraction dosing regimens in the pelvic venous pain relief. Int Angiol. 
2021;40(3):180-186. https://doi.org/10.23736/s0392-9590.21.04579-x  
6. Gültaşli NZ, Kurt A, Ipek A, Gümüş M, Yazicioğlu KR, Dilmen G, Taş I.The relation 
between pelvic varicose veins, chronic pelvic pain and lower extremity venous 
insufficiency in women. Diagn Interv Radiol. 2006 Mar;12(1):34-38. 
7. Pokrovsky AV, Ignatiev IM, Bredikhin RA, Gradusov EG. Postoperative recurrencies of 
varicose veins. Angiologiya i sosudistaya khirurgiya. 2015;21(4):118-125 [in Russian]. 
8. Whiteley AM, Taylor DC, Dos Santos SJ, Whiteley MS. Pelvic venous reflux is a major 
contributory cause of recurrent varicose veins in more than a quarter of women. J Vasc 

13 
 
Surg 
Venous 
Lymphat 
Disord. 
2014;2(4):411-415. 
https://doi.org/10.1016/j.jvsv.2014.05.005  
9. Asciutto G, Mumme A, Asciutto KC, Geier B. Pelvic vein incompetence influences pain 
levels in patients with lower limb varicosity. Phlebology. 2010;25(4):179-183. 
https://doi.org/10.1258/phleb.2009.009014 
10. Foong LC, Gamble J, Sutherland IA, Beard RW. Altered peripheral vascular response of 
women with and without pelvic pain due to congestion. BJOG. 2000 Feb;107(2):157-164. 
https://doi.org/10.1111/j.1471-0528.2000.tb11684.x  
11. Bora A, Avcu S, Arslan H, Adali E, Bulut MD. The relation between pelvic varicose veins 
and lower extremity venous insufficiency in women with chronic pelvic pain. JBR-BTR. 
2012;95(4):215-221. 
12. Kirienko AI, Gavrilov SG, Karalkin AV, Butenko OV, Kapranov SA, Novikov SA. 
Diagnosis of varicose veins of the pelvis. Annaly khirurgii. 2003;4:51-56 [in Russian]. 
13. Gavrilov, S.G., Karalkin, A.V., Turischeva, O.O. Compression treatment of pelvic 
congestion 
syndrome. 
Phlebology. 
2018;33: 
418-424. 
https://doi.org/10.1177/0268355517717424  
14. Gavrilov SG, Turischeva OO. Conservative treatment of pelvic congestion syndrome: 
indications 
and 
opportunities. 
Curr 
Med 
Res 
Opin. 
2017;33:1099-1103. 
https://doi.org/10.1080/03007995.2017.1302414  
 
Safety of study and treatment 
In a case of the development of VAD-treatment-related side effect or adverse event, the patient 
informs an investigator about this within 24 hours. The case is registered, and all necessary 
measures are taken to eliminate this side effect or adverse reaction. Depending on the nature and 
severity of the side effect or adverse reaction, the principal investigator makes a decision on the 
necessity to change the VAD treatment regimen or to discontinue it. 
 
Follow-up period  
Each patient will be followed-up for 2 months after the end of the study in order to exclude the 
occurrence of any side effects or adverse events, and to assess changes in the efficacy of performed 
treatment with time. 
 
Data processing and statistical analysis 
Based on the data from individual CRFs, the MS Excel tables will be created, and then the analysis 
of the data of interest will be performed. Statistical analysis will be carried out using MS Excel, 

14 
 
Statistica 6.0 software and the VassarStats online calculator (open-source project). The arithmetic 
mean (M) and standard deviation (SD) will be calculated. For comparisons with categorical 
variables, the Fisher's exact test will be used. For comparisons with continuous variables, the 
Student's t test or Mann-Whitney U test will be used as appropriate. Differences will be considered 
statistically significant at P value less than 0.05. 
 
Presentation of the results and publication ethics 
In addition to publishing the results of the study in scientific journals, making presentations at 
scientific forums and conferences, it is planned to use the results of this study when developing 
guidelines of the Ministry of Health and posting information about the study results on social 
networks. The leading role in publications belongs to S.G. Gavrilov. The publications will include 
names of E.P. Moskalenko, A.V. Alenichev and A.S. Grishenkova. 
 
Duration of the study 
The duration of the project is determined by achieving the required (150 patients) number of 
participants. The period of a patient's participation in the study, that includes clinical examinations, 
DUS, and the VAD treatment course, is 2 months. Investigators will be examining the patients 
before and 2 months after the VAD treatment course. 
 
Expected issues 
The issues with patient recruitment are expected, as the female patients with CPP are most often 
seen and treated by gynecologists. To solve this problem, information letters will be sent to 
antenatal clinics and outpatient facilities, and interaction will be established with gynecological 
hospitals. No financial issues are expected, as the study is carried out as part of the University's 
research program and does not imply any additional funding. 
 
Responsibilities of investigators  
Principal investigator Prof. Sergey Gavrilov: 
Recruitment of patients, carrying out DUS, randomization of patients, prescription of treatment to 
the patients, and control of the patients’ eligibility for the study, according to the selection criteria, 
the completion of documentation, and compliance with ethical standards. 
 
Dr. Ekaterina Moskalenko, investigator: 
Carrying out DUS of the pelvic veins, completion of documentation, and statistical analysis of the 
data. 

15 
 
 
Dr. Alexander Alenichev, investigator: 
Recruitment of patients, prescription of treatment to the patients, completion of documentation, 
repeated clinical examinations of the patients, and statistical analysis of the data.  
 
Dr. Anastasia Grishenkova, investigator: 
Recruitment of patients, prescription of treatment to the patients, completion of documentation, 
repeated clinical examinations of the patients, and statistical analysis of the data.  
 
Patient information form 
Study title: «Comparative assessment of the efficacy and safety of venoactive drug treatment of 
pelvic venous disorder: results of a single-center prospective randomized trial» 
Facility: Pirogov Russian National Research Medical University. 
 
Introduction 
Before you agree to participate in this study, it is very important that you read and understand the 
explanation of all proposed procedures. This document describes the aim, methods, benefits, and 
inconveniences related to this study. This document also describes other procedures that may be 
offered to you, and you have a right to withdraw from the study at any time. There can be no 
guarantees or confidence in the results of the study. 
Nature and aim of the study 
You are proposed to take part in a single-centre, prospective, randomized trial, the main purpose 
of which is to evaluate the efficacy of various venoactive drugs in the treatment of pelvic venous 
disorder. This study includes female patients with symptomatic pelvic varicose veins, 
accompanied by characteristic symptoms and signs (chronic pelvic pain, pain during and after 
sexual intercourse, heaviness and discomfort in the lower abdomen, frequent urination, the 
presence of varicose veins on the external genitalia). All patients who have signed informed 
consent will undergo a clinical examination by highly professional doctors, ultrasound 
examinations of the pelvic veins, which are necessary to verify the diagnosis, and study of 
abnormalities in the pelvic veins. 
Study methods 
Assessment of the clinical status, obtaining information about medical history and complaints, the 
assessment of pain using a visual analogue scale, physical examination, assessment of local status, 
and duplex ultrasound scanning of the pelvic veins. 
Treatment methods 

16 
 
Study participants will be advised to take a venoactive drug (MPFF 1000, Diosmin 600 or 
Hesperidin + Diosmin 1000, by your random choice) for 2 months at the specific recommended 
dosage. As a study participant, you must fulfill certain requirements, namely: read a product label 
of the prescribed venoactive drug, take the venoactive drug at the same time every day for 2 
months, inform the attending physician (investigator) about any side effect or adverse event that 
are indicated in the product label, assess every 7 days the intensity of your chronic pelvic pain by 
self-rating on the visual analogue scale, according to the instructions and explanations of the 
investigator given to you in advance. You must also report any changes in your physical or mental 
condition during the study. 
Possible risks and inconveniences 
While taking a venoactive drug, rare side effects and adverse events indicated in the product label 
can occur. These include, in particular, pain in the upper abdomen, nausea, diarrhea, skin rash, 
itching, headaches, dizziness, malaise, isolated swelling of the face, lips, eyelids. If these 
symptoms and signs occur, you must immediately consult a doctor and inform the investigator. 
Findings 
Any important information that will be obtained during the study that may affect your health will 
be available to you. 
Voluntary participation/withdrawal 
Your participation in this study is voluntary. The refusal to participate in it will not affect your 
further treatment in this medical institution, and all the medical care that you need will be provided 
in full. You can withdraw from the study at any time, and if so, you must inform your doctor 
immediately. Your doctor may exclude you from the study, if you do not follow your doctor's 
advices, if you are found to be ineligible for the study, if the study is terminated, or for 
administrative reasons. 
Expected benefit 
Venoactive drug treatment of pelvic venous disorder is an effective, safe and not burdensome 
method for patients. Taking a venoactive drug effectively relieves symptoms of pelvic venous 
disorders such as chronic pelvic pain, pain during sexual intercourse, heaviness and discomfort in 
the lower abdomen. The treatment duration depends on the severity of the disease and disturbances 
of the venous blood flow in the pelvic veins identified during clinical examination (ultrasound 
study), but usually does not exceed 2 months. The study will help determine which venoactive 
drug is most effective in relieving pelvic pain and other symptoms of pelvic venous disorder. The 
results of this study have not only scientific, but also significant practical implications. 
Confidentiality 

17 
 
All medical records and study materials that identify you will be kept confidential and will not be 
made public in accordance with applicable laws. If the research results are published in the medical 
literature, your “incognito” mode will be kept and your identity will not be disclosed. 
Monitors, auditors, representatives of the Ethics Committee and official authorities will receive, 
subject to confidentiality of information, access to original medical documents in order to verify 
the correctness of the clinical trial procedures and by signing the Informed Consent Form, you 
consent for this access. 
For all questions regarding the examination and treatment offered to you for varicose veins of the 
pelvis, as well as for additional information, you can contact the investigators:  
Prof. Sergei Gavrilov (mobile phone: +7(916)9299947); Ekaterina Moskalenko (mobile phone: +7 
(985) 4100545); Alexander Alenichev (mobile phone: +7 (926) 2921111); Anastasia Grishenkova 
(mobile phone +7 (926) 1131119). 
 
 
 

18 
 
Informed consent form 
Informed consent 
I (full name), ___________________________________________________________________ 
was informed by the doctor-investigator (full name) ____________________________________ 
_____________________________________________________________________________ 
about all aspects of the planned clinical trial. 
I received information about the aim and objectives of this clinical trial, information about 
examination and treatment methods, the nature of ultrasound studies and venoactive treatment, its 
positive and negative aspects, the benefits and risks of participating in a clinical trial, and about 
my rights and responsibilities. I have been warned about possible complications and adverse events 
during venoactive drug treatment, and about my actions in the event of these complications. 
I had an opportunity to discuss with the doctor-investigator all the questions that interested me and 
was satisfied with the answers I received. 
I am informed that I will be included in the study only after I have undergone a complete 
examination (in accordance with the Protocol) and my medical and physical condition meets the 
criteria of eligibility for this study. 
I voluntarily and consciously agree to participate in a clinical trial on evaluation of the efficacy of 
diosmin-containing venoactive drugs in the treatment of pelvic venous disorder, and I am informed 
that I have the right to refuse from or discontinue participation in this study at any time. 
I agree to follow instructions, cooperate in good faith with the doctor-investigator, and 
immediately report to him/her about any problems with my health. 
I am informed that if my health is harmed by the use of venoactive drug treatment or a medical 
procedure included in the plan of clinical and ultrasound examinations, I will be provided with 
medical care, the costs of which will be reimbursed by the insurance company with which I am 
insured. 
I am informed that information about me and the results of my examination will be confidential 
and can only be disclosed to official representatives while maintaining anonymity. 
By signing this Informed Consent form, I give my permission to access the medical data obtained 
in the study by those responsible for conducting the clinical trial, representatives of the Ethics 
Committee, and official representatives of the Ministry of Health of the Russian Federation. 
I received a signed and dated copy of the Patient Information Form with a 5-page Informed 
Consent Form. 
 
Patient's signature: 
Patient's full name: 
 

19 
 
Date 
(to be completed by the patient) 
 
 
Investigator’s signature: 
 
Investigator’s full name: 
 
 
Date 
(to be completed by the investigator) 
 
Funding 
The study has no special funding. The study will be carried out as part of the research activity of 
the Pirogov Russian National Research Medical University. 
Other project support 
No. 
Links to other projects 
No. 
Participation in other research projects 
The principal investigator and other investigator are not involved in other projects. 
Funding and insurance 
The study has no sponsors or special funding. Insurance of doctors and patients is carried out on 
the general principles of compulsory medical insurance in Russia.