Efficacy and Safety of Sulodexide in the Treatment of Chronic Primary Venous Disease of the Lower Extremities: A Randomized Placebo-Controlled Double-Blind Clinical Trial
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 290
- 试验地点
- 19
- 主要终点
- Revised Venous Clinical Severity Score (rVCSS)
研究概览
简要总结
This study compares the efficacy and safety of sulodexide (Vessel) to placebo in patients with chronic venous disease of the lower extremities.
The primary hypothesis is that more patients will achieve a decrease in rVCSS score of at least 4 points with sulodexide than with placebo.
详细描述
Chronic venous disease (CVD) prevalence is increasing in developed countries. The frequency reported in different sources ranges between 10 and 50% of the population and its rise is expected resulting from the overall aging of the population. The most common symptoms of Chronic venous disease of lower extremities include, increased limb fatigue, heaviness and swelling, pain, cramps, itching, and trophic skin changes that can result in a venous ulcer. CVD has a significant impact on the patient's quality of life and their work productivity.
Conservative treatment consists of lifestyle measures, compression therapy and use of venoactive drugs (venopharmaceuticals). Venoactive drugs are a heterogenous group of compounds with various mechanisms of action, such as increasing venous wall tonus, reducing capillary fragility and permeability, increasing capillary resistance, and improving lymphatic drainage. The goal of the treatment is anti-oedematous action, improvement of trophism of affected tissues, reduction of subjective symptoms, swelling of the limbs and affecting related trophic skin changes which leads to the increase of quality of life.
Sulodexide has protective effect on the endothelium, antithrombotic, fibrinolytic and anti-inflammatory effects. In the last 20 years, it has been well established in the common practice and its efficacy and safety have been demonstrated notably in the treatment of venous diseases such as post-thrombotic syndrome of the lower extremities, secondary prevention of deep and superficial venous thrombosis, supportive treatment of leg venous ulceration, ischemic disease of the lower limbs; symptomatic therapy of intermittent claudication, treatment of diabetic ulcers and microcirculation disorders of various aetiology. Patients with CVD were shown to respond quickly to sulodexide therapy in single arm observational studies. Sulodexide seems to provide both symptomatic and causal therapy. The aim of the present study is to provide the first high-level (causal) evidence on the efficacy and safety of sulodexide across the whole spectrum of patients suffering from symptomatic primary CVD (CEAP classification C2S to C6S).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosed primary venous disease of the lower limbs in stage C2 - C6 according to the CEAP classification, clinical involvement of the venous system of the lower limbs is verified by duplex ultrasonography
- •Presence of objective and subjective symptoms of the disease (classified according to rVCSS score ≥ 4)
- •At the time of the enrolment, patient is not using nor planning to use compression therapy from his own decision or the decision of the treating physician
- •The patient signed an informed consent for inclusion in the clinical trial and consent to the processing of personal data
- •Patient over 18 years of age
- •Male or female patient of non-childbearing potential, i.e.: post-menopausal (at least 2 years without spontaneous menses) or surgically sterile (bilateral tubal occlusion or hysterectomy or ablation of both ovaries); OR of childbearing potential but with a negative pregnancy test result at Visit 1 AND agrees to use a highly effective method of contraception
排除标准
- •Use of a drug with venoactive effect in the last month
- •Regular use of compression therapy or use of mechanical devices for reduction of oedema in the last month
- •Heart Failure as per NYHA III and IV, congestive heart failure with peripheral oedemas
- •Chronic kidney disease with GF < 30 ml/min (< 0,5 ml/s) and/or proteinuria > 0,5 g/24 hours, nephrotic syndrome, renal oedemas
- •Advanced liver disease (Child-Pugh B and C or laboratory values of ALT or AST more than 3 times upper limit of normal range)
- •Deep venous thrombosis lower limb thrombosis and / or documented residual venous obstruction or deep venous reflux due to post-thrombotic changes in the deep venous system
- •Superficial venous thrombosis of the lower limbs in the previous 6 months
- •Congenital venous / venolymphatic venous malformation
- •Neuropathy of any aetiology
- •Diabetic foot syndrome
- •Refractory (uncontrollable) arterial hypertension (inability to achieve therapeutically systolic blood pressure ≤ 160 mmHg or diastolic blood pressure ≤ 100 mmHg)
- •Symptomatic ischemic disease of lower limbs
- •Lymphoedema: primary, posttraumatic, postoperative, post-radiation, malignant
- •Manual/instrumental lymphatic drainage in the last 6 months
- •Invasive procedure on the lower limbs in the last 6 months
- •Trauma of the lower extremity that has not fully healed
- •Use of oral/parenteral anticoagulants, dual antiplatelet therapy, diuretics, corticosteroids, oestrogens, or progesterone and its derivates
- •Chronic pain treatment ≥ 14 days
- •Psychopharmaceuticals affecting fluid retention (antipsychotics, combined antidepressants)
- •Pathologic obesity (BMI > 40 kg/m2)
- •The patient is currently enrolled in another interventional or non-interventional study
- •Contraindications to the administration of sulodexide according to IB (haemorrhagic diathesis, hypersensitivity to the drug substance or any of the excipients, heparin, heparinoids or other glycosaminoglycans (GAGs), etc.)
- •Patients with active malignant disease or malignant disease in remission for less than 5 years
- •Pregnancy
- •Breastfeeding
- •Continuous exclusion criteria:
- •Clinically significant progression of the investigated condition, which requires urgent or early invasive therapy (as assessed by the investigating physician)
- •Onset of any condition requiring initiation of the not permitted medication/treatment
- •Serious adverse reactions
- •Pregnancy
- •Compression therapy can be initiated anytime during the trial participation in case that patient experiences worsening of the rVCSS score of at least 4 points compared to baseline AND the treating physician decides to prescribe such regimen. Certified/notified compression stockings of class II (23-32 mmHg) based on circular knit are allowed. Patients initiating compression therapy are not excluded but the stocking need to be taken off a day before the scheduled study visit. The treatment allocation in patients initiating compression therapy remain blinded.
- •In case compression therapy is initiated during study participation, information about the date of initiation, type and adherence is collected in the following visits.
- •If sufficient proportion of subjects is switched to compression therapy, compression therapy will be tested as effect modifier across CEAP classes.
研究组 & 干预措施
Sulodexide arm
Name: Vessel (medicinal product registered in Italy) Dosage form: soft capsules Active substance: sulodexidum 250 LSU Dosage: 2 x 2 soft capsules daily (oral use), in line with the labelled posology (500 LSU twice a day) Duration: 24 ± 4 weeks
干预措施: Vessel (Drug)
Placebo arm
Dosage form: soft capsules Appearance: undistinguishable from the active Dosage regimen: 2 x 2 soft capsules daily Duration of placebo intake: a total of 24 ± 4 weeks
干预措施: Placebo (Drug)
结局指标
主要结局
Revised Venous Clinical Severity Score (rVCSS)
时间窗: 24 weeks of treatment
A minimal decrease in rVCSS score by 4 points will be considered a clinically significant response to treatment.
次要结局
- Work Productivity and Activity Impairment (WPAI questionnaire)(8 and 24 weeks of treatment)
- EQ-5D questionnaire(8 and 24 weeks of treatment)
- Mean time of clinically significant worsening rVCSS(4, 8, 12 and 24 weeks of treatment)
- Volume in lower limb(4, 8, 12 and 24 weeks of treatment)
- Revised Venous Clinical Severity Score (rVCSS)(4, 8 and 12 weeks of treatment)
- Visual Analogue Scale (VAS)(4, 8, 12 and 24 weeks of treatment)
- Chronic Venous Insufficiency Quality of Life (CIVIQ-20 questionnaire)(8 and 24 weeks of treatment)
- Compression therapy initiation(4, 8, 12 and 24 weeks of treatment)