Clinical trial NCT04670432: Resolution Enhancement by a Supplemental Obstruction Lessening Venoactive Drug for Eight Weeks in Deep Vein Thrombosis
Official title: Resolution Enhancement by a Supplemental Obstruction Lessening Venoactive Drug for Eight Weeks in Deep Vein Thrombosis: A Pilot Study to Evaluate if Hydroxyethylrutoside Reduces the Risk of Post-Thrombotic Syndrome in Patients With DVT.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Deep Vein Thrombosis
Keywords: Venoactive drugs
Hydroxyethylrutoside
Venoruton
Thrombus resolution
Residual Vein Obstruction
Post-Thrombotic Syndrome
Lead sponsor: Maastricht University Medical Center
Sponsor class: OTHER
Collaborators: name: Netherlands Thrombosis Foundation
First posted: 2020-12-17
Enrollment: 44
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The RESOLVE-DVT study is a randomized single-center pilot study to determine the effects of hydroxyethylrutoside (Venoruton) on aspects of deep vein thrombosis (DVT) resolution associated with post-thrombotic syndrome (PTS). Based on these results, the investigators will estimate its potential as a preventive therapy for PTS.

Eligible consenting patients who develop an acute, objectively confirmed DVT will be randomized and equally allocated to two trial arms, either the treatment group (Venoruton tablet 500 mg twice daily) or the control group (usual care). The pilot trial consists of 5 study contacts over 12 weeks at which outcome assessment is performed: inclusion, 1 week, 4 weeks, 8 weeks, 12 weeks. Treatment allocation is masked for outcome assessors, but not for patients.

Detailed description: Rationale: After a DVT, one in three patients develops PTS of the affected leg, despite anticoagulant treatment and elastic compression therapy (ECT) in the acute phase of DVT. Considering the major societal burden associated with PTS, supplementation of current prevention with an effective pharmacotherapeutic therapy would be of high value. Since the pathogenesis of PTS is mediated through persistent inflammation during thrombus resolution, causing damage to the vein wall resulting in venous insufficiency, the venoactive flavonoids with their vasoprotective and anti-inflammatory properties provide an excellent candidate. As investigational medicinal product, the highly effective flavonoid Hydroxyethylrutoside (Venoruton) was chosen.

Objective: To assess the effect of Venoruton on PTS-associated aspects of DVT resolution.

Study design: A single-center, randomized, controlled, pilot study.

Study population: Adults presenting themselves at the emergency department (ED) with a first, acute, proximal DVT of the lower extremity. Inclusion will be performed within 48 hours after diagnosis of DVT.

Intervention: Administration of 500 mg Venoruton twice daily for 8 weeks following DVT, in addition to standard treatment by ECT and anticoagulant therapy.

Baseline characteristics: Assessments include demographic data, smoking status, site and extension of DVT, side of affected leg, duration of complaints at time of diagnosis, risk factors for DVT (immobilisation, trauma, etc.), type of ECT, presence/suspicion of pulmonary embolism, concomitant medications.

Main study parameters: The primary study outcome is residual vein obstruction (RVO), assessed by duplex ultrasound (DUS) at 12 weeks after DVT. Main secondary outcomes are levels of circulating biomarkers and severity of PTS-characterizing clinical signs at baseline, 1 week, 4 weeks, 8 weeks and 12 weeks. Moreover, we measure quality of life (QoL) and PTS-characterizing symptoms at baseline, 4 weeks and 12 weeks.

Additional study parameters: Medication adherence and ECT compliance at 1 week, 4 weeks, 8 weeks and 12 weeks. Pill count of Venoruton at 8 weeks. Pill count of direct oral anticoagulant (DOAC) at 12 weeks. The occurrence of relevant (serious) adverse events is assessed at all visits.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Patients have a follow-up duration of 12 weeks after diagnosis of DVT. In addition to their visit at the ED, patients will visit the outpatient clinic four times during follow-up. At each visit secondary outcomes are measured through questionnaires, blood withdrawal and assessment of the affected leg. The first visit coincides with inclusion and two subsequent visits (4 and 12 weeks) coincide with the regular clinical care pathway. The primary outcome, RVO, is measured at 12 weeks after DVT by DUS. Patients allocated to the intervention group will take two oral tablets daily over a period of eight weeks. Venoruton has been established as safe with rarely occurring, mild, reversible side-effects through many years of experience.

Masking: while patients are aware of their treatment allocation, the physicians and researchers are not, as to provide unbiased outcome assessment.

Eligibility criteria: Inclusion Criteria:

* Adult, defined as ≥ 18 years of age
* Objectively confirmed DVT by DUS
* Proximal DVT, defined as iliofemoropopliteal venous thrombosis
* Acute DVT, defined as having symptoms for ≤ 7 days at presentation
* Willing and able to give written informed consent

Exclusion Criteria:

* Previous DVT
* Bilateral DVT
* Pre-existent chronic venous insufficiency (CEAP-criteria C ≥ 3)
* Active malignancy, inflammatory disease (e.g. rheumatoid arthritis), or immunosuppressive therapy
* Current pregnancy or breast feeding
* Indication for therapeutic thrombolysis
* Contra-indication for DOAC

Primary outcomes:
measure: Residual Vein Obstruction
timeFrame: At 12 weeks
Secondary outcomes:
measure: Levels of circulating biomarkers
timeFrame: At time of inclusion, 1 week, 4 weeks, 8 weeks and 12 weeks
measure: Clinical sign severity
timeFrame: At time of inclusion, 1 week, 4 weeks, 8 weeks and 12 weeks
measure: Symptom severity
timeFrame: At time of inclusion, 4 weeks and 12 weeks
measure: VEINS Quality of Life/Symptoms (VEINES-QOL/Sym)
timeFrame: At time of inclusion, 4 weeks and 12 weeks
measure: Short Form 36 Health Survey (SF-36)
timeFrame: At time of inclusion, 4 weeks and 12 weeks
measure: Euro Quality of Life 5D (EQ-5D)
timeFrame: At time of inclusion, 4 weeks and 12 weeks
Other outcomes:
measure: Medication adherence
timeFrame: At 1 week, 4 weeks, 8 weeks and 12 weeks
measure: Adherence to elastic compression therapy
timeFrame: At 1 week, 4 weeks, 8 weeks and 12 weeks
measure: Pill counts Venoruton
timeFrame: At 8 weeks, which is the end of Venoruton treatment
measure: Pill count of DOAC
timeFrame: At 12 weeks
measure: (Serious) adverse events
timeFrame: At inclusion, 1 week, 4 weeks, 8 weeks and 12 weeks.
Locations:
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
state: Limburg
Study officials:
affiliation: Maastricht University Medical Center
name: Arina J ten Cate - Hoek, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: ten Cate-Hoek AJ, Henke PK, Wakefield TW. The post thrombotic syndrome: Ignore it and it will come back to bite you. Blood Rev. 2016 Mar;30(2):131-7. doi: 10.1016/j.blre.2015.09.002. Epub 2015 Oct 9.