A randomised, double-blind, parallel-group, placebo-controlled phase III study to evaluate the efficacy and safety of desmoteplase in subjects with acute ischemic stroke.

Acute ischemic stroke is a major cause of mortality and of long-term
disability. Thrombolysis targets the clots that occlude brain vessels in acute
ischemic stroke and therefore has the potential to provide significant
improvement of clinical outcome. The only thrombolytic intervention currently
approved for acute ischemic stroke needs to be administered within 3 hours
after symptom occurrence, and has a significant risk inducing intracerebral
haemorrhage. Desmoteplase has properties that indicate potential for a better
clinical efficacy and a lower risk of bleeding that may allow extension of the
time window for treatment to 9 hours after symptom onset.

The primary objective of the study is to evaluate the efficacy of desmoteplase
90µg/kg versus placebo in terms of favourable outcome at Day 90 in subjects
with acute ischemic stroke. Secondary objectives are to evaluate: the efficacy
of desmoteplase 90µg/kg versus placebo in terms of favourable outcome at Day
7/Discharge and Day 30 in subjects with acute ischemic stroke, the efficacy of
desmoteplase 90µg/kg versus placebo in terms of favourable outcome at Day 90 in
the subgroup of patients with a baseline core-lesion volume < 25 cc,
recanalisation associated with 90µg/kg versus placebo in the subgroup of
patients with follow-up angiography at 12-24 hours, safety and tolerability of
desmoteplase, incidence of symptomatic intracranial haemorrhage (sICH),
mortality in the treatment groups, immunogenicity of desmoteplase,
pharmacokinetics/pharmacodynamics of desmoteplase, impact of treatment on
subject's quality of life, impact of treatment on utilization of resources.

The study will be conducted as a prospective, randomised, double-blind,
placebo-controlled, multinational, multi-centre, parallel-group study.
Study duration per subject will be 90 days from the time of the Investigational
Medicinal Product (IMP) administration.
The study will investigate one dose of desmoteplase (90µg/kg) versus placebo
given as a single intravenous bolus.
A diagnostic neuroimaging screening with MRI or CT will be used to identify
eligible subjects with occlusion or high grade stenosis in proximal cerebral
arteries and with no signs of extensive infarction, intracranial haemorrhage or
subacute infarctions. After eligibility and baseline assessments, subjects will
receive treatment with the IMP within 3-9 hours after the onset of stroke
symptoms. In the subsequent hours and days patients will undergo regular safety
and efficacy assessments until they are discharged. Study
procedures/examinations will be performed between 0.5 and 9 hours, between 12
and 24 hours after IM administration, at Day 7 or discharge (if earlier), at
Day 30 and at Day 90.
An imaging scan 12-24 hours after IMP administration will be used to mintor
subjects for intracranial bleedings, to assess infarct size, and in subjects
ondergoing a folow-up angiogram (optional), to assess recanalisation.

90µg/kg desmoteplase, or placebo, administered as a single intravenous bolus
injection during 1-2 minutes.

At baseline a physical and neurological examination will be performed. Blood
pressure, pulse rate and weight will be assessed. An ECG will be recorded, and
blood samples will be taken for safety laboratory tests. A diagnostic MRI or
perfusion CT scan will be conducted. In case of eligibility study medication
will be administered as a single IV bolus injection during 1-2 minutes. As
follow-up over a 90 day period (7 assessments/visits), blood sampling will take
place 6 times, vital signs will be assessed 7 times, one ECG wil be recorded,
one MRI/CT scan will be conducted, and various rating scales will be assessed
2-5 times. At the final visit the physical/neurological examination will be
repeated.
Major risk of thrombolysis is the occurrence of intracerebral haemorrhage,
which occurred in 3.5% of the patients treated with desmoteplase 90µg/kg in
previous clinical studies (refer to IB).
Benefit of participation is a potential clinical improvement in a patient
group, suffering from a life threatening and disabling disorder, who currently
have insufficient adequate treatment modalities available.