Clinical trial NCT03413618
Conditions: Deep Vein Thrombosis Postthrombotic Syndrome
Keywords: deep vein thrombosis postthrombotic syndrome anticoagulation treatment prevention
Sponsor: Pirogov Russian National Research Medical University
Start date: 2017-12-20; Completion date: 2019-07-31
Enrollment: 90 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The randomized clinical study aimed to assess the efficacy and safety of standard anticoagulation with rivaroxaban in combination with diosmin compared to the isolated use of standard rivaroxaban for prolonged therapy of acute femoro-popliteal deep vein thrombosis reflected the speed of deep vein recanalization and incidence of post-thrombotic syndrome.

Detailed description:
Deep vein thrombosis is an acute inflammatory disease that affects vein wall and leads to the structural changes in the wall and valves reflected with chronic venous insufficiency that called postthrombotic syndrome (PTS).

Diosmin as a flavonoid agent has properties to reduce leukocyte-endothelial interaction and inflammatory response, that could reduce the damage to venous wall and valves.

The hypothesis of the study is based on assumption that diosmin combined with standard anticoagulation can improve outcomes of femoro-popliteal DVT due to increase speed of veins recanalization, decrease of vein wall inflammation and finally decrease the incidence of PTS at 6 month and 1 year after index DVT.

Arms: arm 1: treatment of deep vein thrombosis with anticoagulation (rivaroxaban), elastic compression stockings and additional prescription of diosmin arm 2: standard treatment of deep vein thrombosis with anticoagulation (rivaroxaban) and elastic compression stockings
Interventions: intervention 1: Rivaroxaban intervention 2: Diosmin intervention 3: compression stockings
Intervention descriptions: intervention 1: 15 mg b.i.d. for 3 weeks and then 20 mg q.d. up to 6 month intervention 2: 600 mg q.d. for 12 month intervention 3: above knee stocking for 12 month

Protocol documents:
Prot_SAP_000.pdf: 
Translation from Russian 
STUDY PROTOCOL 
Title of the study: The efficacy of Rivaroxaban with Diosmine in the long-term 
treatment of acute proximal deep vein thrombosis 
Brief title: Rivaroxaban With Diosmine in Long-term Treatment of DVT 
(RIDILOTT-DVT) 
Sponsor: Pirogov Russian National Research Medical University 
Clinical center: Clinical Hospital no.1 of the President’s Administration of Russian 
Federation 
Principle Investigator: Associated professor Ilya Schastlivtsev 
Term of execution: 2018-2019 
Th aim: to evaluate the efficacy of using disomine in combination with rivaroxaban 
compared with the isolated use of rivaroxaban during long-term treatment of acute 
proximal deep vein thrombosis. 
Study design: a single-center open-label randomized clinical trial with blinded 
outcome assessor 
Inclusion and exclusion criteria 
Inclusion criteria:  
•
Age over 18 years
•
The first episode lower limb DVT
•
The absence or presence of clinical provocation of DVT (except active
oncological process)
•
Thrombosis verification using duplex scan
•
Localization of thrombotic occlusion not below the popliteal vein and not
above the inguinal fold
•
Signed informed consent to participate in the study
Exclusion criteria: 
•
Suspicion of pulmonary embolism
•
Verified pulmonary embolism
•
Bilateral DVT
•
Contraindications to the use of rivaroxaban (in accordance with the official
instructions)


• Contraindications to the use of Diosmin (in accordance with the official 
instructions) 
• Active oncological process 
• Verified severe thrombophilia (APS, AT-3, protein C, S deficiency) 
• The use of other anticoagulants for more than 7 days from the time of 
DVT verification 
• The inability to use compression stockings after 3 days from the time of 
DVT verification 
• Performed surgery on superficial or deep veins of the lower extremities 
(thrombolysis, thrombectomy, vein ligation, cava filter implantation) 
• Constant use of other drugs that affect the hemostasis system (except for 
ASA in a dose of not more than 100 mg). 
• Low compliance 
 
Methods of diagnostic 
 
The initial examination of patients with suspected DVT will be carried out 
within the first 4 hours after admission to the hospital and will include a physical 
examination to determine the clinical signs of acute deep vein thrombosis of the 
lower extremities, as well as all possible individual risk factors for venous 
thromboembolic complications. The integral clinical probability for DVT will be 
determined using a two-level Wells scale. If there is a high clinical probability for 
DVT duplex ultrasound scan (DUS) will be performed to verify the diagnosis. If 
there is a low clinical probability for DVT, the D-dimer level will be measured, if it is 
found to be elevated it will be followed by DUS. If an DVT is identified by DUS, its 
initial characteristics will be recorded in a special card (Appendix 1). 
 
If a patient meets the inclusion and exclusion criteria, as well as after he signed 
the informed consent, he will be randomly assigned to the main or control group. If 
the patient is unconscious, informed consent may be signed by the patient’s 
authorized person (immediate family). 
 
Methods of randomization 
The randomization will be performed by number of medical record: if the last 
digit is even - the patient is included in the main group, odd - in the control, zero - the 
previous digit is taken into account. 
 
Methods of treatment 
In both groups, standard conservative treatment for DVT will be conducted, 
including the use of rivaroxaban in a dosage of 15 mg twice daily for 3 weeks with a 
further transition to a single dose of 20 mg once daily. During the initial therapy for 
DVT will be allowed to use parenteral anticoagulants up to 7 days. All patients will 
not be allowed to use other drugs that affect the blood coagulation system, except of 
acetylsalicylic acid (ASA) in a dose of not more than 100 mg / day. Also, all patients 


require to receive compression stockings of 20-30 mm of Hg within 3 days after DVT 
verification. 
In the control group, only standard c conservative treatment, including 
rivaroxaban and compression stockings, will be used. The anticoagulation with 
rivaroxaban will be stopped at 6 months, and the use of compression stockings will 
be prescribed up to 12 months. 
In the main group, in addition to the standard treatment (rivaroxaban for 6 
months and elastic compression stockings for 12 months), the Diosmin will be used 
at a dose of 600 mg (Phlebodia 600) once daily in a continuous mode for the entire 12 
months. 
Early termination of treatment and the withdrawal of patients from the study is 
possible due to the development of serious adverse events and complications of 
therapy (major bleeding, clinically relevant non-major bleeding, which required 
temporary discontinuation of the drug), as well as gross violations of compliance. In 
the event of minor and minor, but clinically significant bleeding that does not require 
discontinuation of drugs, the patient will be monitored as part of the study. 
Follow up 
Patients will be followed up to 12 months with monthly clinical examination to 
identify possible complications of therapy, a violation of the regimen of medication 
and a compliance with the elastic compression protocol. Also, every 2 months, a 
DUS will be performed according to the protocol with the results recorded in a 
specially designed map (Appendix 1). 
At 6 and 12 months the presence and severity of the PTS by the Villalta scale, 
the severity of CVD by the rVCSS scale and the quality of life according to the 
CIVIQ-20 questionnaire (Appendix 2) will be assessed. Also, after 12 months, the 
final DUS will be performed to assess the final degree of recanalization. The nature 
of the activities carried out with the dynamic observation of the patient is presented in 
Table 1. 
DUS will be performed before the patient is included in the study and then every 
2 months throughout the entire treatment period. The study will include a graphical 
depiction of the thrombus burden, the distal and proximal thrombus border (in cm 
from the floor level), and the degree of recanalization of the venous segments. 
Recanalization of the venous segments will be assessed at three main levels: popliteal 
vein, femoral vein, common femoral vein, based on the degree of compressibility of 
the venous segment. The degree of compressibility of the venous segment will be 
calculated as the ratio of the difference between the diameter of the vein without 
compression and the diameter of the vein with maximum compression to the diameter 
of the vein without compression. For each venous segment, the degree of 
recanalization at the narrowest point will be taken into account. 


Table 1. The content of follow-up
Baseline 1 m 
2 m 
3 m 
4 m 
5 m 
6 m 
7 m 
8 m 
9 m 
10 m 
11 m 
12 m 
Clinical 
investigatio
n 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
DUS 
+ 
+ 
+ 
+ 
+ 
+ 
+ 
Villalta 
+ 
+ 
rVCSS 
+ 
+ 
CIVIQ-20 
+ 
+ 
Endpoints of the study 
Primary efficacy endpoint: the frequency of PTS at 12 months by the Villalta 
scale (5 points or more). 
Secondary efficacy endpoints: 
•
The severity of CVD by rVCC score at 6 and 12 months
•
Quality of life by CIVIQ-20 at 6 and 12 months
•
The degree of recanalization of the venous segments at 6 and 12 months of
complex treatment
•
Dynamics of recanalization of venous segments bi-monthly
Safety endpoints: 
•
Any adverse event (including overall mortality)
•
Major adverse event (including major bleeding)
•
Bleeding event:
o Major bleeding by ISTH:
Recorded hemoglobin drop by more than 20 g/l
The need for blood transfusion of 2 or more doses of erythrocytes
Bleeding resulting in death
Bleeding in anatomically significant areas (brain, spinal cord,
retroperitoneal space, pericardial cavity, joint cavity, intraocular,
intermuscular hematoma
o Clinically relevant non-major bleeding: any bleeding that does not meet
the criteria for major, but required the cancellation of the anticoagulant,
and / or the implementation of hemostatic measures, and / or


hospitalization in the hospital, and / or unscheduled treatment to the 
doctor. 
o Minor bleeding: any bleeding that does not meet the criteria of a major
and/or CRNM, did not require the suspension of therapy and changes in
the patient's lifestyle
Power calculations 
The frequency of PTS detection in 12-24 months after verification of DVT is 
20-50% (Kahn 2002). According to preliminary data, the use of Diosmin in
combination with rivaroxaban compared to the isolated use of rivaroxaban for 12
months in patients with ileo-femoral thrombosis can reduce the severity of CVD
symptoms by 1.5-2 times (Kuznetsov MR 2016). Thus, with the error of the first kind
- 0.05 and the error of the second kind of 0.2, the initial 12-month incidence of
PTS development at the level of 30% and its expected decrease by 3 times, the
number of patients in two comparable groups should be 60 people, and total sample
size - 120 patients. It is possible to complete the study earlier if the level of
statistical significance of the differences obtained is reached. Intermediate statistical
processing is planned for the recruitment of 30 patients each group.
A statistical analysis plan 
Comparing the total frequency of occurrence of endpoints in the main and 
control groups using Fisher's exact test, comparing the probability of occurrence of 
endpoints over the observation period using Kaplan-Meier statistics, calculating the 
risk of developing PTS using Cox regression, comparing mean values of scoring 
systems for assessing the severity of the disease and quality of life using the t-test, 
comparing the dynamics of changes in the degree of recanalization by venous 
segments using general liner model for the repeated measures. 
November 11, 2017 
Principle investigator 
Ilya Schastlivtsev 


Appendix 1 
Clinical Hospital no.1 of the Presidents Administration of Russian Federation
РPirogov Russian National Researching Medical University 
Duplex ulrasound scan
Date:
            Name: 
Age: 
Conclusion: