Oral direct factor Xa inhibitor rivaroxaban in patients with acute symptomatic deep-vein thrombosis or pulmonary embolism using a strong CYP 3A4 inducer.

Rivaroxaban is a new anticoagulant drug that is currently being tested in a
large group of patients with DVT or PE. Under normal circumstances, the dose of
rivaroxaban for the treatment of DVT or PE is 15 mg twice daily for 3 weeks
followed by 20 mg once daily for a longer period of time. However, the effect
of rivaroxaban can be influenced by medication that belongs to the group of the
so-called strong CYP 3A4 inducers. Examples of strong CYP 3A4 inducers are
carbamazepine, phenytoin, rifampicin/rifampin, and rifabutin. If a patient uses
such a strong CYP inducer in combination with rivaroxaban, then the effect of
rivaroxaban will be substantially less, possibly making the treatment of DVT or
PE less effective. The aim of this study is to demonstrate that in patients who
use a strong CYP inducer, the rivaroxaban dose needs to be higher than normal
for achieving the same therapeutic effect as in patients who use rivaroxaban in
the absence of a strong CYP 3A4 inducer.

The purpose of this study is to demonstrate that in patients with DVT or PE who
use a strong CYP 3A4 inducer, the use of this higher rivaroxaban dose results
in a similar rivaroxaban concentration in the blood and a rivaroxaban induced
blood thinning effect than observed in patients that use the normal rivaroxaban
dose in the absence of a strong CYP 3A4 inducer.

Additionally, the occurrence of symptomatic recurrent venous thromboembolism
and major and clinically relevant non-major bleeding will be documented.
After the whole study is finished, your doctor will be informed on the study
results in general. Your doctor will discuss these with you if requested. If
there are issues concerning your particular health status your doctor will be
discuss these with you. This will not happen immediately after you have
finished taking part in the study but will take some time due to the analysing
of results.

De Einstein CYP 13238 study is a multicentre cohort study evaluating an adapted
rivaroxaban dose regimen in patients with acute, proximal deep-vein thrombosis
or acute pulmonary embolism and concomitant use of a strong CYP 3A4 inducer for
the entire 3-month study duration.

After inclusion all participating patients receive 30 mg twice daily during 3
weeks followed by rivaroxaban 20 mg twice daily. All patients will have a
30-day observational period after cessation of treatment.

For this study, participating patients will be asked to attend the center for 6
study visits; during these visits blood samples will be taken: on day 1 (1
blood sample), day 15 (3 blood samples), day 30 (1 blood sample), day 60 (2
blood samples), day 90 (1 blood sample). Day 121 a follow-up is planned; on day
8 a contact by telephone.
Each study visit takes approximately 2 to 3 hours; the visit on day 15 (3 blood
samples) may take 3 to 4 hours.

The study treatment takes 3 months, followed by an observational period of 1
month.

Since rivaroxaban is a blood thinner it may be associated * like all other
blood thinners - with an increased risk of bleeding. These bleedings might be
minor and insignificant but, in rare cases, bleeding can involve an organ and
can be severe or even fatal. The risk of bleeding may be increased in patients
with high blood pressure (i.e. arterial hypertension) and/or on concomitant
drugs which also prevent the clotting of blood (including drugs like Aspirin
and other common drugs to relieve pain).

Rivaroxaban has already been tested in healthy volunteers and patients. The
dose of rivaroxaban which will be used in this study appeared to be as
effective and safe as the standard way of treatment without the need for
regular laboratory monitoring of the anti-clotting effect. Rivaroxaban may turn
out to be more or less effective than the standard treatment with enoxaparin
and warfarin or acenocoumarol. If rivaroxaban is less effective, this will be
noticed as soon as possible and the treatment will be changed immediately by
the investigator.

The safety of rivaroxaban 10 mg has been evaluated in several studies including
three phase III studies in patients undergoing major orthopedic surgery of the
legs (total hip replacement or total knee replacement) treated during up to 39
days. In these studies, rivaroxaban was compared to enoxaparin, a commonly used
blood thinner. Commonly (>1%) reported adverse drug reactions were anemia,
nausea, increase in liver enzymes (like ALT, AST, GGT) and bleeding
complications after surgery. Less frequently, an increase was found in
bilirubin (a blood break-down product) and in enzymes (i.e. lipase and amylase)
which break down food components.

It is not yet known if the study drug could affect an unborn child. Women who
are able to conceive and who decide to take part must agree to take adequate
contraception throughout the study and be checked for pregnancy using urine
tests.

As the study drug is under development there may be side effects that are not
yet known and have not yet been reported. Therefore the patient is asked to
notify your doctor, or any of the study staff, of any new symptoms that may
appear.