A Phase III case series clinical study of the reversal of the anticoagulant effects of dabigatran by intravenous administration of 5.0g idarucizumab (BI 655075) in patients treated wtih dabigatran etexilate who have uncontrolled bleeding or require emergency surgery or procedures.

currently there is no commercially available drug to reverse the
anticoagulation effect of dabigatran.
for emergency situations with subjects using dabigatran, there is need for a
drug to quickly reverse the anticoagulation effect of dabigatran.

An antidote was developed, acting on the dabigatran in the blood, and reversing
the the anticoagulation effect of dabigatran.
this drug is called idarucizumab.

during previous studies in toal 110 subjects were treated with idarucizumab
(doses between 20 mg and 8000 mg), administered in 5 to 60 minutes by
intravenous injection.

From this studies it showed that the effect was nearly direct, and no
observations nor laboratory parameters indicated that it would be possible to
overdose a subject.
Based on these results 5 gram idarucizumab was chosen as the best dose to
investigate within this trial, for all subjects.

to investigate the safety and efficacy of idarucizumab in reversing the
anticoagulation effect of dabigatran, in patients who have uncontrolled
bleeding or require emergency surgery or invasive procedures.

Based on the results mentioned in chapter "background" this trial will
investigate 5 gram idarucizumab (or 10 gram, if applicable) for all patients.
This trial will thus be open-label, single arm.
Subjects will be evaluated as their own control group (instead of more arms
within a study) by means of labevaluations prior to the administration of
antidote, between the 2 antidote vials, and at various timepoints after the
antidote administration.

A lot of the patients suitable for the trial, will be brought into the hospital
through Emergency Room (ER). few will already be admitted and might require
unplanned emergency procedures. to make sure all subjects potentially suitable
for the trial are described correctly here, they will be referred to as
"brought in" from now on.

within the protocol there is a distinction between population A (patients who
are taking dabigatran, and have uncontrolled/life threatening bleeding
requiring urgent medical intervention) and B (patients who are taking
dabigatran who may not be bleeding, but do require an emergency surgery or
precedure for a condition other than bleeding). regardless of population A or
B, all subjects will have the possibility to be treated with a participating
site.

when subjects are brought in, their condition will be evaluated by a physician,
to determine the need for an antidote (inclusion/exclusion criteria) + the use
of dabigatran is confirmed.
When the need for treatment is decided and consented upon (see section informed
consent process) the antidote will be administered.

Prior, during and after administration of the antidote, labparameters will be
taken for PK/PD and safety determinations. all details could be found in
protocol flowchart. In the rare case an additional dose of 5 gram idarucizumab
is administered labparameters will again be taken or PK/PD and safety analysis.

After approximately 24 hours (visit 3) restart of anticoagulation can be
evaluated + the selected drug/dose will be documented.

Patients will be followed up untill 90 days (visit 6) after administration of
vial 2 for safety and labevaluations.

every patient will receive 1 administration of open label treatment with 5 gram
idarucizumab, to reverse the anticoagulation effect of dabigatran.
this dose will be intravenously administered through 2 vials of 50ml each, max
15 minutes apart.

In rare cases in which the bleeding does not seize after 5 gram idarucizumab
the investigator may administer an additional dose of 5 gram idarucizumab.

Burden for patients will mainly be caused by the first 24 hours after being
brought in.
Burden will consist of frequent blood draws surrounding the administration of
the antidote

Patients will be given the choice to participate, or not to participate tot his
trial. There is no comparable alternative for the study drug with the same
effect within the same timeframe.
Subjects might experience this as a burden.

Patients might be brought in, in a condition that somebody else (see section
informed consent) will decide for them about study participation. Subjects
might experience this as a burden.

Patients will be under extra care of their research physician for 90 days
following the administration of the antidote. The first 24 hours will be most
time consuming, but as this coincides with the admission a subject is exposed
to anyway due to it*s condition, this will not take more time than whilst not
participating into the study.

Depending on a subject*s condition, the time investment expected after visit 3
is fairly little, but this may vary from subject to subject.

The to be expected risks are low, as described in the patient information
sheet.
The consist of risks with blood draws, ECG, allergic reactions, interactions
with other drugs, early discontinuation, pregnancy&breastfeeding and unforeseen
risks.

Increasing the dose to 10 gram did not show any effect on adverse event numbers
based on pre-clinical and clinical data.