Randomised, double-blind, placebo-controlled, single-dose, dose-escalation study of the safety, tolerability, and pharmacokinetics of Lu AA24493 in acute ischemic stroke

Acute ischemic stroke is a major cause of mortality and of long-term
disability. The only intervention currently available is limited to
thrombolysis within 3 hours after symptom onset. Lu AA24493 (CEPO) is
chemically modified erythropoietin (EPO), by cabamylation of lysine residues.
It has been hypothesized that erythropoietin may have cytoprotecive properties
in case of ischemia. Animal models have shown a time-window of at least 24
hours.

Objective of this first human study with Lu AA24493 is to evaluate the safety,
tolerability, immunogenicity and pharmacokinetics of Lu AA 24493 in patients
with acute ischemic stroke. In addition patient outcome on National Institutes
of Health Stroke Scale (NIHSS) en modified Rankin Scale (mRS) will be followed.

The study is an international multi-centre, randomised, double-blind,
placebo-controlled, single-dose, dose-escalation study. Patients will be
randomised to receive a single dose of Lu AA24493 or placebo in the following
dose-escalation scheme: 0.005mg/kg (1 active: 1 placebo); 0.05mg/kg (1 : 1);
0.5mg/kg (3 : 1), 5mg/kg (3 : 1), 50mg/kg (3 : 1). Each dosing panel will be
completed before progression to the next panel. Patients will be randomised by
means of a central randomisation system (CRAN). This system will ensure a
period of at least 48 hours between randomisation of patients to active
treatment. Patients will be under continuous supervision for 4 hours after
administration of each dose and are to stay in the hospital for at least 72
hours. Patients will be followed-up for 30 days. Patients showing an antibody
response will be followed for an additional 6 months.

One single dose of Lu AA24493 or placebo, administered as an IV infusion.

At Baseline medical/neurological history is taken, temperature, blood pressure,
pulse rate, height and weight are assessed; an ECG is recorded, and blood
samples are taken for laboratory testing. A physical and neurological exam are
conducted. NIHSS and mRS are assessed. IMP is administered as one single IV
infused dose. After IMP administration blood samples are taken at 13 occasions
for PK analysis. After 24, 48 and 72 hours, after 7 days (or at discharge
whichever comes first), and after 30 days, temperature, blood pressure and
pulse rate are assessed, and an ECG is recorded. Blood samples are taken for
laboratory testing. After 7 and 30 days, weight is recorded, a physical and
neurological exam is conducted, and NIHSS and mRS are assessed. Fourteen days
after IMP administration blood samples are taken for laboratory testing. Blood
sampling will take place after 2, 3, 4, 5, and 6 months in patients, showing an
antibody response. At each study visit AEs and concomitant medication are
recorded.
Except for the normal risks, associated with study procedures like regular
blood sampling, the most important risk, anticipated for this study, is
eliciting an antibody response due to administration of a (modified)
glycoprotein drug.
Benefit of participation is a potential clinical improvement in patients,
suffering from a life threatening and disabling disorder, for whom currently no
treatment modality is available.