Resolution Enhancement by a Supplemental Obstruction Lessening Venoactive Drug for Eight Weeks in Deep Vein Thrombosis

Deep Vein Thrombosis Clinical Trial

— Resolve-DVT  

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04670432
• Other study ID #: NL73142.068.20
• Status: Completed
• Phase: Phase 3
• Start date: December 8, 2020
• Est. completion date: November 28, 2023

Study information

• Verified date: February 2024
• Source: Maastricht University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 44
• Est. completion date: November 28, 2023
• Est. primary completion date: November 28, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Deep Vein Thrombosis
• Postthrombotic Syndrome
• Thrombosis
• Venous Thrombosis

Intervention

Drug:
• Hydroxyethylrutoside
500 mg film-coated tablet

Locations

Country	Name	City	State
Netherlands	Maastricht University Medical Center	Maastricht	Limburg

Sponsors (2)

Lead Sponsor	Collaborator
Maastricht University Medical Center	Netherlands Thrombosis Foundation

Country where clinical trial is conducted

Netherlands, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Medication adherence	Using a medication adherence score, which is answered directly by the patient.	At 1 week, 4 weeks, 8 weeks and 12 weeks
Other	Adherence to elastic compression therapy	Question regarding frequency of use and reason for deviation, which are answered directly by the patient.	At 1 week, 4 weeks, 8 weeks and 12 weeks
Other	Pill counts Venoruton	In patients allocated to the intervention group, an unblinded assessor will perform a pill count of Venoruton tablets, which will be compared to the amount of tablets that should have been administered.	At 8 weeks, which is the end of Venoruton treatment
Other	Pill count of DOAC	In all patients, a pill count of the DOAC tablets will be performed and compared to the total amount of tablets that should have been administered.	At 12 weeks
Other	(Serious) adverse events	The occurrence of relevant (serious) adverse events is assessed at all visits.	At inclusion, 1 week, 4 weeks, 8 weeks and 12 weeks.
Primary	Residual Vein Obstruction	Transversal vein diameter =2mm on duplex-ultrasound during full compression, which is assessed by a radiologist blinded for study allocation. A secondary assessment based on acquired images will be performed by an independent expert radiologist, again blinded for study allocation.	At 12 weeks
Secondary	Levels of circulating biomarkers	A panel of biomarkers, associated with RVO and PTS, will be measured in venous blood at several time-points. These include markers of inflammation (e.g. IL6, IL10), cell adhesion (e.g. ICAM1, P-selectin), and remodelling (e.g. MMPs). Differences for each individual biomarker over time will be compared between groups.	At time of inclusion, 1 week, 4 weeks, 8 weeks and 12 weeks
Secondary	Clinical sign severity	Objective Villalta score + circumference calf and ankle, which is measured by an assessor blinded to study allocation. Compared to the contralateral unaffected leg.	At time of inclusion, 1 week, 4 weeks, 8 weeks and 12 weeks
Secondary	Symptom severity	Subjective Villalta score, which is answered directly by the patient through a survey	At time of inclusion, 4 weeks and 12 weeks
Secondary	VEINS Quality of Life/Symptoms (VEINES-QOL/Sym)	This disease-specific quality of life score is answered directly by the patient through a survey.	At time of inclusion, 4 weeks and 12 weeks
Secondary	Short Form 36 Health Survey (SF-36)	This general quality of life score is answered directly by the patient through a survey.	At time of inclusion, 4 weeks and 12 weeks
Secondary	Euro Quality of Life 5D (EQ-5D)	This general quality of life score is answered directly by the patient through a survey.	At time of inclusion, 4 weeks and 12 weeks