Study of Antiinflammatory Effects of Detralex (Daflon)

Study of Antiinflammatory Effects of Detralex (Daflon) in Patients With Chronic Venous Disease

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).

Study Overview

• Status: Completed
• Conditions: Chronic Venous Insufficiency
• Intervention / Treatment: Drug: Detralex

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).

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 4

Contacts and Locations

Study Locations

• Croatia
  • Zagreb, Croatia, 10000
    • University Hospital Dubrava

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Detralex; Detralex 500 mg twice daily for three month prior to surgery	Drug: Detralex; Detralex 500 mg twice daily for three month prior to surgery; Other Names: Daflon
No Intervention: Not taking Detralex; Not taking Detralex for three months prior to surgery

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	14 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	14 months

Collaborators and Investigators

• Sponsor: University Hospital Dubrava
• Collaborators: Servier
• Investigators: Principal Investigator: Marko Ajduk, PhD, University Hospital Dubrava

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: August 1, 2012
• Primary Completion (Actual): May 1, 2019
• Study Completion (Actual): September 1, 2019

Study Registration Dates

• First Submitted: July 24, 2012
• First Submitted That Met QC Criteria: July 27, 2012
• First Posted (Estimate): July 31, 2012

Study Record Updates

• Last Update Posted (Actual): November 1, 2019
• Last Update Submitted That Met QC Criteria: October 31, 2019
• Last Verified: October 1, 2019

More Information

Terms related to this study

• Keywords: inflammation; varicose veins
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Venous Insufficiency
• Other Study ID Numbers: Detra-001-Ajd

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No