Clinical trial NCT05851183: Effect of Vitis Vinifera Seed Extract on Venous Reflux Time in Varicose Vein
Official title: A Prospective, Open-label, Pragmatic Randomized Controlled Trial to Demonstrate the Effect of Improving the Venous Reflux Time by Vitis Vinifera Seed Extract in Patients With Varicose Vein of Lower Extremity
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Varicose Veins of Lower Limb
Lead sponsor: Yonsei University
Sponsor class: OTHER
First posted: 2023-05-09
Enrollment: 200
Sex: ALL
Minimum age (years): 19
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The investigators aim to compare and evaluate the improvement effects on venous reflux time in patients with lower extremity varicose veins between lifestyle modifications and the combined treatment of Vitis Vinifera seed extract (Entelon®) administration and lifestyle modifications.
Primary purpose: TREATMENT

Brief summary: The number of patients with lower extremity varicose veins has been increasing due to an aging population, with treatments divided into conservative and invasive methods. Current treatments can be expensive and inaccessible for some patients. Entelon, a relatively inexpensive intravenous drug, has shown promise in improving symptoms related to venous lymphatic dysfunction, but its objective vascular function improvement hasn't been proven. This study aims to assess the effectiveness of Vitis Vinifera seed extract (Entelon®) combined with lifestyle therapy in patients with varicose veins, using follow-up Doppler ultrasonography to measure venous reflux improvement.

Detailed description: Varicose veins in the lower extremities are more than the function of the valve membranes on the inside of the legs, and the heart cannot function, resulting in regurgitation in the lower half of the body. This causes blood to pool in the lower extremities and causes various symptoms. Large stalks of superficial veins and venous valves of deep veins become dysfunctional, resulting in an increase in blood vessels in the calf area with backflow of blood. The valvular insufficiency of lower extremity veins is the main cause. In general, it occurs in the great saphenous vein that flows into the deep vein from the groin, the small saphenous vein in the posterior leg, and the perforating vein in the calf. Reflux in superficial veins (e.g. great saphenous vein, small saphenous vein) and deep veins can generally be confirmed using Doppler ultrasound. Determine the direction of treatment by confirming if there is branch vein dilatation. Ultrasonography is also done on the opposite, unaffected side, even if symptoms are in only one leg.

Treatment of varicose veins can generally be divided into conservative treatment and invasive treatment, and lifestyle correction and wearing compression stockings are recommended as conservative treatment. Surgical treatment is indicated when conservative treatment is ineffective or interferes with daily life. Symptoms can be alleviated by removing superficial veins with regurgitation due to valvular insufficiency, or by inducing hardening of the causative blood vessels using high frequency or laser to block regurgitation and prevent blood flow.

However, most of these treatments are non-salary items, and are relatively expensive treatment methods that impose a large financial burden on patients. In addition, deep veins are responsible for 90% of blood transport, but surgical treatment is impossible and only conservative treatment is possible.

As a non-invasive treatment, which is an intravenous active agent, is registered as a drug to be administered, and improvement of symptoms related to venous lymphatic dysfunction (pain, lower extremity anxiety symptoms) is attracting attention. It is relatively inexpensive compared to surgical treatment, but until now, objective improvement of vascular function by drug treatment has not been proven. Vitis Vinifera seed extract (Entelon®) was launched in 1998 and its safety has already been confirmed, and the investigators have investigated the effect of lower limit volume reduction compared to placebo after administration of Vitis Vinifera seed extract in patients with edema. (Sano A, Tokutake S, Seo A. Proanthocyanidin-rich grape seed extract reduces leg swelling in healthy women during prolonged sitting. J Sci Food Agric. 2013 Feb;93(3):457-62.).

In this study, along with lifestyle therapy in patients with varicose veins, follow-up Doppler ultrasonography after administration of Entelon will be used to confirm the improvement effect of venous reflux.

Eligibility criteria: Inclusion Criteria:

1. Adult males and females aged between 19 and under 80 years old
2. Patients with the following findings on venous Doppler ultrasound examination:

   * Superficial veins (such as the great saphenous vein, small saphenous vein, etc.) showing valvular reflux for 0.5 seconds or longer
   * Deep veins (such as the femoral vein, etc.) showing valvular reflux for 1 second or longer
3. Patients who have completed the washout period as described below by Visit 2, including the screening period:

   * Analgesics, steroids, anti-inflammatory drugs, and venoactive medications (such as Entelon, etc.): at least 4 weeks
4. Patients who voluntarily provide written informed consent to participate in this clinical trial

Exclusion Criteria:

1. Peripheral arterial occlusive disease in the lower limbs
2. Asymptomatic lower extremity varicose veins
3. Acute deep vein thrombosis
4. Frequent lower limb pain due to neuropathy
5. Patients who have undergone or are scheduled for varicose vein procedures/surgeries (However, patients who have had a procedure or surgery more than 1 year prior to the screening date are eligible to participate)
6. Patients diagnosed with systemic diseases causing edema or thrombosis, such as heart failure, endocrine diseases (hypothyroidism, Cushing's syndrome, uncontrolled diabetes), allergic reactions to medications, urticaria and angioedema, malabsorption and protein-calorie malnutrition, obstructive sleep apnea, or thrombophilia, as determined by the investigator
7. History of malignancy within the past 5 years, but the following cases are eligible for clinical trial participation:

   * Those who have a history within the past 5 years but maintain a cured state without recurrence or metastasis
   * Those who have completed treatment for their tumor and have been disease-free for at least 5 years from the screening date
   * Those who have passed at least 1 year since the screening date after complete resection of basal cell carcinoma/squamous cell carcinoma, radical resection of thyroid papillary cancer, or successful treatment of cervical intraepithelial neoplasia
8. Severe renal dysfunction (serum creatinine levels more than twice the normal upper limit of the institution) at the screening date
9. Severe liver dysfunction (ALT or AST levels more than three times the normal upper limit of the institution) at the screening date
10. Need to receive diuretics or contraindicated medications and therapies that may affect the results of this clinical trial during the study period (However, patients who have been taking antihypertensive medications (calcium channel blockers, beta-blockers, angiotensin-converting enzyme inhibitors, vasodilators, vasoconstrictors) at the same dosage for at least 4 weeks (28 days) before screening and will maintain the same dosage and administration during the study period are eligible to participate)
11. History of clinically significant psychiatric disorders or alcohol abuse
12. History of hypersensitivity reactions to the investigational drug or its ingredients
13. Those who have participated in or are scheduled to participate in other clinical trials (investigational drugs, medical devices, health functional foods) within 12 weeks from the screening date
14. Pregnant or breastfeeding women
15. Women of childbearing potential who plan to become pregnant during the clinical trial participation period
16. Individuals deemed unsuitable for participation in the clinical trial by the investigator

Primary outcomes:
measure: Change in venous reflux time
timeFrame: 6, 12 weeks
Secondary outcomes:
measure: Improvement of venous reflux
timeFrame: 6, 12 weeks
measure: Change in varicose vein size area
timeFrame: 6, 12 weeks
measure: Change in venous reflux volume
timeFrame: 6, 12 weeks
measure: Change of extracellular water ratio
timeFrame: 6, 12 weeks
measure: Improvement in Venous Clinical Severity Score (VCSS)
timeFrame: 6, 12 weeks
measure: Improvement of 14-item Chronic Venous Insufficiency quality of life Questionnaire (CIVIQ-14)
timeFrame: 6, 12 weeks
Other outcomes:
Locations:
city: Yongin
country: Korea, Republic of
facility: Yongin Severance Hospitall, Yonsei University College of Medicine
state: Gyeonggi-do
Study officials:
affiliation: Yongin Severance Hospital, Yonsei University College of Medicine
name: In Hyun Jung, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gloviczki P, Lawrence PF, Wasan SM, Meissner MH, Almeida J, Brown KR, Bush RL, Di Iorio M, Fish J, Fukaya E, Gloviczki ML, Hingorani A, Jayaraj A, Kolluri R, Murad MH, Obi AT, Ozsvath KJ, Singh MJ, Vayuvegula S, Welch HJ. The 2022 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 I. Duplex Scanning and Treatment of Superficial Truncal Reflux: Endorsed by the Society for Vascular Medicine and the International Union of Phlebology. J Vasc Surg Venous Lymphat Disord. 2023 Mar;11(2):231-261.e6. doi: 10.1016/j.jvsv.2022.09.004. Epub 2022 Oct 12.
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