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Study of Antiinflammatory Effects of Detralex (Daflon)

Primary Purpose

Chronic Venous Insufficiency

Status
Completed
Phase
Phase 4
Locations
Croatia
Study Type
Interventional
Intervention
Detralex
Sponsored by
University Hospital Dubrava
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Chronic Venous Insufficiency focused on measuring varicose veins, inflammation

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Chronic venous disease (CEAP 2 and 3) and saphenofemoral insufficiency

Exclusion Criteria:

  • Previous deep venous thrombosis
  • Previous or acute thrombophlebitis of the GSV (confirmed by duplex findings - morphologic changes of the GSV above the knee)
  • Immunological disorders
  • Diabetes type I or II,
  • Severe inflammatory disease: such as Behcet, lupus, Horton and other arteritis, polyarthritis, spondylarthritis or sclerodermia
  • Recent (less than 3 months) or scheduled non-authorized non-pharmacological treatments:
  • Sclerotherapy,
  • Surgical treatment of varicose veins (crossectomy, phlebectomy),
  • Endovenous treatment (endovenous laser, radiofrequency),
  • Non-authorized pharmacological treatment in the last 3 months and during the study:
  • Anti-inflammatory agents (except acetylsalicylic acid at dose 350 mg daily),
  • Systemic corticosteroids or immunosuppressives,
  • Venoactive drugs including open label MPFF,
  • Pentoxifylline
  • Patients already (at the time of randomization) taking Detralex for symptoms linked to chronic venous disease
  • Arterial insufficiency (absent pedal pulses or ABI < 0.9)
  • Any important clinical or laboratory abnormalities
  • Pregnancy, breastfeeding or wish of becoming pregnant during the study

Sites / Locations

  • University Hospital Dubrava

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

No Intervention

Arm Label

Detralex

Not taking Detralex

Arm Description

Detralex 500 mg twice daily for three month prior to surgery

Not taking Detralex for three months prior to surgery

Outcomes

Primary Outcome Measures

Antiinflammatory Effects of Detralex (Daflon)
The following markers of inflammation will be analyzed: Blood (biochemical analysis): soluble ICAM-1, soluble VCAM-1, E-selectin, L selectin PAI-1, TIMP-1, Angiopoietin-1, Angiopoietin-2 and Tie-2. Vein wall ([immuno]histological and biochemical analysis) : CD 45 (leukocytes), S100 (C-fibers), MMP3, MMP9, SMC (smooth muscle cells). Presence (or not) of microthrombi in the vein lumen

Secondary Outcome Measures

Clinical effects of Detralex (Daflon)
Subjective perception of pain, leg heaviness, cramping and itching will be assessed using visual analogue scale (VAS) graded from 0 to 10. Leg edema will be assessed by measuring the leg circumference. Data will be recorded as follow: three months before the surgery one day before the surgery one week after the surgery one month after bthe surgery three months after the surgery

Full Information

First Posted
July 24, 2012
Last Updated
October 31, 2019
Sponsor
University Hospital Dubrava
Collaborators
Servier
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1. Study Identification

Unique Protocol Identification Number
NCT01654016
Brief Title
Study of Antiinflammatory Effects of Detralex (Daflon)
Official Title
Study of Antiinflammatory Effects of Detralex (Daflon) in Patients With Chronic Venous Disease
Study Type
Interventional

2. Study Status

Record Verification Date
October 2019
Overall Recruitment Status
Completed
Study Start Date
August 2012 (undefined)
Primary Completion Date
May 2019 (Actual)
Study Completion Date
September 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University Hospital Dubrava
Collaborators
Servier

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
Aim of the study: To investigate if there is a differences in expression of inflammatory markers in venous wall and blood among patients treated with Detralex and those not treated with Detralex (control group).
Detailed Description
Chronic venous disease (CVD) represents one of the most common vascular disorder. It's different clinical manifestations (most often seen as varicose veins) can be observed in up to 40% of adult female population and in about 30% of adult males. Different mechanical and biological factors play role in the process of deterioration of venous wall tone and consequent vein valve disfunction that eventually lead to increase venous pressure . Evidence suggest that inflammation has a central place in this process even from the early stage of CVD. Usual symptoms of venous insufficiency are pain, leg heaviness, night cramping, itching, and are often accompanied with leg edema. The extent of clinical manifestation may not correlate with patients' symptoms. Treatment of varicose veins encompasses vein surgery (stripping, phlebectomy, radiofrequency and laser ablation), sclerotherapy and compression therapy. Detralex (in some countries registered as Daflon) is an oral flavonoid that consists of 90% micronized diosmin and 10% flavonoids expressed as hesperidin. Several studies showed some beneficial effects of Detralex in alleviating symptoms in patients with CVD. It may be used in conjunction with surgery, sclerotherapy, or compression therapy or it may be the only therapy when other therapeutical modalities are not indicated or not feasable. Animal studies showed antiinflammatory effects of Daflon in way that Daflon acts favorably on microcirculatory complications by normalizing the synthesis of prostaglandins and free radicals. It decreases bradykinin-induced microvascular leakage and inhibits leukocyte activation, trapping, and migration. However, by searching the available literature (MEDLINE) we found no study that investigated what are the antiinflammatory effects of flavonoids in humans. The aim of this study is to investigate if there is a differences in expression of inflammatory markers in venous wall and blood between patients treated with Detralex and those not treated with Detralex (control group).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Chronic Venous Insufficiency
Keywords
varicose veins, inflammation

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
84 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Detralex
Arm Type
Active Comparator
Arm Description
Detralex 500 mg twice daily for three month prior to surgery
Arm Title
Not taking Detralex
Arm Type
No Intervention
Arm Description
Not taking Detralex for three months prior to surgery
Intervention Type
Drug
Intervention Name(s)
Detralex
Other Intervention Name(s)
Daflon
Intervention Description
Detralex 500 mg twice daily for three month prior to surgery
Primary Outcome Measure Information:
Title
Antiinflammatory Effects of Detralex (Daflon)
Description
The following markers of inflammation will be analyzed: Blood (biochemical analysis): soluble ICAM-1, soluble VCAM-1, E-selectin, L selectin PAI-1, TIMP-1, Angiopoietin-1, Angiopoietin-2 and Tie-2. Vein wall ([immuno]histological and biochemical analysis) : CD 45 (leukocytes), S100 (C-fibers), MMP3, MMP9, SMC (smooth muscle cells). Presence (or not) of microthrombi in the vein lumen
Time Frame
14 months
Secondary Outcome Measure Information:
Title
Clinical effects of Detralex (Daflon)
Description
Subjective perception of pain, leg heaviness, cramping and itching will be assessed using visual analogue scale (VAS) graded from 0 to 10. Leg edema will be assessed by measuring the leg circumference. Data will be recorded as follow: three months before the surgery one day before the surgery one week after the surgery one month after bthe surgery three months after the surgery
Time Frame
14 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Chronic venous disease (CEAP 2 and 3) and saphenofemoral insufficiency Exclusion Criteria: Previous deep venous thrombosis Previous or acute thrombophlebitis of the GSV (confirmed by duplex findings - morphologic changes of the GSV above the knee) Immunological disorders Diabetes type I or II, Severe inflammatory disease: such as Behcet, lupus, Horton and other arteritis, polyarthritis, spondylarthritis or sclerodermia Recent (less than 3 months) or scheduled non-authorized non-pharmacological treatments: Sclerotherapy, Surgical treatment of varicose veins (crossectomy, phlebectomy), Endovenous treatment (endovenous laser, radiofrequency), Non-authorized pharmacological treatment in the last 3 months and during the study: Anti-inflammatory agents (except acetylsalicylic acid at dose 350 mg daily), Systemic corticosteroids or immunosuppressives, Venoactive drugs including open label MPFF, Pentoxifylline Patients already (at the time of randomization) taking Detralex for symptoms linked to chronic venous disease Arterial insufficiency (absent pedal pulses or ABI < 0.9) Any important clinical or laboratory abnormalities Pregnancy, breastfeeding or wish of becoming pregnant during the study
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marko Ajduk, PhD
Organizational Affiliation
University Hospital Dubrava
Official's Role
Principal Investigator
Facility Information:
Facility Name
University Hospital Dubrava
City
Zagreb
ZIP/Postal Code
10000
Country
Croatia

12. IPD Sharing Statement

Citations:
PubMed Identifier
15883226
Citation
Eberhardt RT, Raffetto JD. Chronic venous insufficiency. Circulation. 2005 May 10;111(18):2398-409. doi: 10.1161/01.CIR.0000164199.72440.08. No abstract available.
Results Reference
background
PubMed Identifier
12934755
Citation
Nicolaides AN. From symptoms to leg edema: efficacy of Daflon 500 mg. Angiology. 2003 Jul-Aug;54 Suppl 1:S33-44. doi: 10.1177/0003319703054001S05.
Results Reference
background
PubMed Identifier
21768702
Citation
Sezer A, Usta U, Kocak Z, Yagci MA. The effect of a flavonoid fractions diosmin + hesperidin on radiation-induced acute proctitis in a rat model. J Cancer Res Ther. 2011 Apr-Jun;7(2):152-6. doi: 10.4103/0973-1482.82927.
Results Reference
background
PubMed Identifier
21126890
Citation
Perrin M, Ramelet AA. Pharmacological treatment of primary chronic venous disease: rationale, results and unanswered questions. Eur J Vasc Endovasc Surg. 2011 Jan;41(1):117-25. doi: 10.1016/j.ejvs.2010.09.025. Epub 2010 Dec 3.
Results Reference
background
PubMed Identifier
16193222
Citation
Bergan JJ. Chronic venous insufficiency and the therapeutic effects of Daflon 500 mg. Angiology. 2005 Sep-Oct;56 Suppl 1:S21-4. doi: 10.1177/00033197050560i104.
Results Reference
background
PubMed Identifier
33141449
Citation
Martinez-Zapata MJ, Vernooij RW, Simancas-Racines D, Uriona Tuma SM, Stein AT, Moreno Carriles RMM, Vargas E, Bonfill Cosp X. Phlebotonics for venous insufficiency. Cochrane Database Syst Rev. 2020 Nov 3;11(11):CD003229. doi: 10.1002/14651858.CD003229.pub4.
Results Reference
derived

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Study of Antiinflammatory Effects of Detralex (Daflon)

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