Resolution Enhancement by a Supplemental Open-Label Venoactive drug for Eight weeks in Deep Vein Thrombosis

One in three patients experiences chronic signs and symptoms in the affected
leg after deep vein thrombosis (DVT). This is referred to as the
post-thrombotic syndrome (PTS). Current prevention of PTS is limited to elastic
compression therapy (ECT) in the acute phase of the DVT. Considering the major
societal burden associated with PTS, supplementation of current prevention with
an effective pharmacotherapeutic therapy could be of high value. Since the
pathogenesis of PTS is mediated through inadequate thrombus resolution damaging
the vessel wall and increasing inflammation, the venoactive flavonoids with
their vasoprotective and anti-inflammatory effects provide an excellent
candidate. As an investigational medicinal product (IMP), the highly effective
flavonoid O-β-hydroxyethylrutoside (HR) was chosen.

The central question of this study is *What is the effect of supplementation of
regular therapy with 8 weeks of HR after a first, acute, proximal DVT of the
lower extremity on objective aspects of thrombus resolution which are
associated with the development of PTS?*

To address this aim, the following objectives were formulated:

Primary objective
* What is the effect of additional HR treatment for 8 weeks in combination with
regular therapy on RVO after an acute, proximal DVT of the lower extremity?

Secondary objectives
* What is the effect of additional HR treatment for 8 weeks in combination with
regular therapy on PTS-associated circulating biomarkers after a first, acute,
proximal DVT of the lower extremity?

* What is the effect of additional HR treatment for 8 weeks in combination with
regular therapy on PTS-characterizing symptoms and clinical signs after a
first, acute, proximal DVT of the lower extremity?

* What is the effect of additional HR treatment for 8 weeks in combination with
regular therapy on quality of life after a first, acute, proximal DVT of the
lower extremity?

This pilot study is designed as a single-center, open-label, randomized,
controlled, clinical trial. It will recruit patients who present themselves at
the emergency department (ED) with a first, acute, proximal DVT of the lower
extremity that has been objectively confirmed. Upon inclusion, patients are
randomly allocated evenly between the intervention or control group. Patients
in the intervention group receive treatment with HR for 8 weeks, the duration
of thrombus resolution, and starting within 48 hours after diagnosis of DVT.
Since the outcome measures are objective, there is no need for a placebo
medicine in the control group. All patients receive regular treatment,
consisting of ACT and ECT in accordance with the latest guideline on
antithrombotic therapy by the Dutch internist association. During a follow-up
period of twelve weeks, patients are seen five times: on baseline (<48h after
diagnosis of DVT) and after 1 week, 4 weeks, 8 weeks and 12 weeks at the
outpatient clinic. At all these visits, secondary outcomes are measured by
anamnesis, blood drawing and assessment of the affected leg. At the last visit,
the primary outcome measure is determined by echography. Visits at 4 and 12
weeks and echography can be combined with the regular clinical care pathway.

Investigational treatment
Patients in the intervention group receive therapy with HR (one tablet of 500
mg twice daily for 8 weeks) in combination with regular treatment. Patients in
the control group only receive regular treatment (consisting of ACT and ECT).
No placebo medicine will be used in this study.

Use of co-intervention
Subject can use co-medication and other interventions if in accordance with
usual care (e.g. stop antiplatelet drugs during ACT).

Escape medication
Subjects are allowed to use analgesics when experiencing pain of the affected
leg in accordance with usual care (e.g. NSAID discouraged regarding bleeding
risk).

Name and description of investigational product
The IMP for this study is HR, produced by GlaxoSmithKline under the tradename
Venoruton®. It has market authorization and is registered as a medicine in the
Netherlands. Its official indication is symptomatic treatment of CVI. Thus, our
study utilizes a marketed IMP for a new indication.

Summary of findings from non-clinical studies
This is discussed in the Summary of Product Characteristics (SPC).

Summary of findings from clinical studies
This is discussed in the SPC.

Summary of known and potential risks and benefits
This is discussed in the SPC.

Description and justification of route of administration and dosage
In its medicinal form, HR is only available as a film-coated tablet of 500 mg
administered by oral route. Its recommended dosage in CVI is 1000-1500 mg
daily. [36] Its half-life varies between individual from 10 to 25 hours. [36]
We opted for twice daily ingestion of a 500 mg tablet. Since most patients will
receive take their anticoagulant twice daily (hospital preference for
Apixaban), twice instead of once daily ingestion of the IMP is not expected to
influence treatment adherence.

Dosages, dosage modifications and method of administration
One film-coated tablet of Venoruton® is administered twice-daily by oral route.
Dosage modifications are not applicable.

Preparation and labelling of Investigational Medicinal Product
The clinical pharmacy of Radboud University Medical Center prepares and labels
the IMP in accordance with the Good Manufacturing Practice (GMP) guideline.

Drug accountability
Once prepared and labelled, the IMP is delivered and stored at the clinical
pharmacy of the azM. Patients allocated to the intervention group will receive
and start treatment with the IMP within 48 hours after diagnosis. The IMP is
picked up at the clinical pharmacy by the researcher and delivered to the
patient. Every patient receives 4 boxes of the IMP at once, each containing 30
tablets in medicine strips (2 daily x 7 days x 8 weeks = 112 required tablets).
Upon treatment completion after 8 weeks, patients return these boxes upon their
visit to the clinic. The researcher returns these boxes to the clinical
pharmacy, where a pill count is performed to provide an estimate of compliance.
Subsequently, the clinical pharmacy will destroy the remaining IMP.

Patients have a follow-up duration of 12 weeks after diagnosis of DVT. In
addition to their visit at the ED, subjects will visit the outpatient clinic
four times during follow-up. At each visit secondary outcomes are measured
through standardized forms, anamnesis, blood drawing and assessment of the
affected leg. Two visits (4 and 12 weeks) coincide with the regular clinical
care pathway. The primary outcome, RVO, is measured at 12 weeks by echography
and is also part of the regular care. Subjects allocated to the intervention
group will take two oral tablets daily over a period of eight weeks. The IMP
has been established as safe with rarely occurring, mild, reversible
side-effects through many years of experience.