DOI 10.

1007/s00702-004-0248-2
J Neural Transm (2005) 112: 415–428

Neuroprotective treatment with Cerebrolysin in patients

with acute stroke: a randomised controlled trial

G. Ladurner1, P. Kalvach2 , H. Moessler3, and

the Cerebrolysin Study Group4
1
Department of Neurology, Christian-Doppler Hospital, Salzburg, Austria
2
Department of Neurology, Charles University, FNKV, Prague, Czech Republic
3
EBEWE Pharma, Unterach, Austria
4
See Appendix for a listing of the members of the Cerebrolysin Study Group

Received May 11, 2004; accepted October 18, 2004

Published online December 7, 2004; # Springer-Verlag 2004

Summary. Background and purpose. Cerebrolysin is a compound with neuro-

trophic and neuroprotective activity. It is produced by enzymatic breakdown of
purified brain proteins and consists of low molecular weight peptides and amino
acids. Cellular and animal models of cerebral ischaemia have shown that it is a
potent neuroprotective agent. We explored the safety and preliminary outcome
of Cerebrolysin treatment in patients with acute stroke. Methods. Randomised,
placebo-controlled, parallel group trial. Patients with acute stroke were random-
ised within 24 h of stroke onset to IV therapy with placebo or Cerebrolysin
50 mL=day for 21 days. Both groups received concomitant treatment with
ASA 250 mg=day PO and pentoxifylline 300 mg=day IV. Clinical examinations
were performed on days 1, 3, 7, 21 and 90 post baseline. Outcome measures were
the Canadian Neurological Scale, the Barthel Index, the Clinical Global Impres-
sions, the Mini-Mental State Examination, and the Syndrome Short Test. Treat-
ment emergent adverse events, lab tests, and vital signs were recorded to assess
the safety of Cerebrolysin. Results. 146 patients were enrolled in two groups: 78
Cerebrolysin and 68 placebo. At baseline, no significant group differences were
observed. Patients in the Cerebrolysin group had no significant improvement
in the CNS score, the Barthel Index and the Clinical Global Impressions when
compared to the placebo group. A significant improvement of cognitive function
of the patients on Cerebrolysin was observed in the Syndrome Short Test when
compared to the placebo group. Cerebrolysin was well tolerated and safe.
Adverse events occurred with a similar frequency in both groups. Conclusion.
The results demonstrate that neurotrophic treatment with Cerebrolysin is safe
and well tolerated by patients with acute stroke. The findings, despite the small
sample size, also indicate a potential treatment effect of Cerebrolysin in acute
stroke. Larger studies, however, are needed to confirm and extend these findings.
416 G. Ladurner et al.

Keywords: Acute stroke, neuroprotection, clinical trial, stroke therapy,

Cerebrolysin.

Introduction
Acute stroke is a leading cause of adult disability and has a worse prognosis for
survival than most forms of cancer. In recent years, considerable efforts have been
devoted to the development of new therapeutic strategies for acute stroke victims.
Thrombolytic therapy through early intervention with recombinant tissue
plasminogen activator (rTPA) within 3 h of the onset of the stroke has been shown
to limit neurological damage and improve outcome (NINDS, 1995). Unfortu-
nately, thrombolytic therapy has practical value in only a small proportion of
patients and it bears a considerable risk of symptomatic intracranial hemorrhage.
Apart from thrombolysis, two large scale clinical studies have investigated
the effects of aspirin (CAST, 1997; IST, 1997) and heparin therapy (IST, 1997)
in acute stroke. While a very limited, but significant effect of Aspirin on reduc-
ing fatalities after acute stroke has been observed in both studies, no significant
functional improvement could be achieved with Aspirin treatment in stroke sur-
vivors. The heparin treatment regimen for acute stroke did not result in any
meaningful clinical benefit in the IST trial. In view of the minimal benefit
that can be achieved with Aspirin treatment and the practical limitations of
thrombolysis, the currently available treatment options for stroke victims are
clearly unsatisfactory.
Thus, substantial effort has been expended to the development of neuropro-
tective therapies that intervene at various stages of the ischaemic cascade and
which potentially have a wider clinical application. Several classes of com-
pounds have been tested, including calcium channel blockers, N-methyl-D-
aspartate (NMDA) antagonists, glutamate release inhibitors, anti-adhesion
antibodies (anti-ICAM 1), GM-1 gangliosides,
-butyric acid antagonists, so-
dium channel blockers, glycine antagonists, free oxygen radical scavengers, and
potassium channel agonists, among others (De Keyser, 1999; Clark, 2001;
Sacco, 2001; Martinez-Vila, 2001). A few of these compounds are still under
clinical investigation, but all clinical trials available to date have delivered
disappointing results and some showed safety problems (Squire, 1996; Davies,
1997; Enlimomab Acute Stroke Trial Investigators, 2001). Since all these com-
pounds have delivered convincing results in experimental animal stroke models,
it has been speculated, that the current design of clinical stroke studies is not
suitable for the investigation of neuroprotective substances, and the predictive
value current animal models for the development of new stroke therapies has
been questioned (Parsons et al., 2000).
The use of neurotrophic factor and stem cell therapy for stroke has also been
considered. Basic fibroblast growth factor (bFGF), brain derived neurotrophic
factor (BDNF), insulin-like growth factor (IGF) and osteogenic protein-1 have
been studied. The therapeutic potential has convincingly been shown for bFGF
and osteogenic protein-1. Both factors achieved improvement of behavioural
outcome and a reduction of infarct size in animal models (Kawamata, 1997,
1998; Schaebitz, 1997; Lin, 1999). In clinical trials, bFGF (Trafermin) was well
 Neuroprotection with Cerebrolysin in acute stroke 417

tolerated, but a subsequent phase III study was stopped with negative results
(FIBLAST safety study group, 1998; Clark, 2000). Lately, the transplantation
of neuronal stem cells or the induction and stimulation of endogenous neuro-
genesis after brain ischaemia has been discussed as a potential treatment for
stroke and stroke regeneration.
Cerebrolysin is a peptide preparation for IV infusion which mimics the
action of neurotrophic factors. The compound is produced by a biotechnologi-
cal process, a controlled hydrolysis of purified brain proteins, and consists of
low-molecular-weight neuropeptides and free amino acids. Cerebrolysin has
been shown to exert neurotrophic as well as neuroprotective effects in vitro
and in vivo. It induces neurite outgrowth (Satou et al., 1994, 2000) and reduces
apoptosis triggered by growth factor withdrawal in cultivated neurons (Hartbauer,
2001). In a recent study in rats, Cerebrolysin has been shown to increase
the number of neuronal progenitor and to enhance neurogenesis in the dentate
gyrus of adult animals which correlated with improved spatial memory perfor-
mance in these animals (Tatebayashi et al., 2003). Neuroprotective effects of
Cerebrolysin have been demonstrated in models of excitotoxicity in vitro
(Hutter-Paier et al., 1996) and in vivo (Veinbergs et al., 2000). Further, it has
been shown to ameliorate the effects of oxidative cell stress in animals follow-
ing to ischaemia (Gonzales et al., 1998; Sugita et al., 1993). On a molecular
level, an inhibitory effect of Cerebrolysin on calpain has been demonstrated
(Wronski et al., 2000). In animal models of stroke, intravenous Cerebrolysin
reduced mortality by about 50% after bilateral carotid artery occlusion in rats
(Schwab et al., 1997) and reduced infarct size as well as the loss of MAP-2
immunoreactivity in a model of middle cerebral artery occlusion (Schwab,
1998). The latter findings have recently been confirmed and extended by Frey
(2002). In this study, intravenous Cerebrolysin, in a dose-dependant manner,
decreased infarct volume by about 60%, significantly reduced the neurological
deficit of the treated animals, and reduced mortality by 59%.
Clinically, Cerebrolysin is widely used for the treatment of Alzheimer’s
Disease (Ruether et al., 2001) and preliminary clinical studies with stroke
patients have indicated a potential therapeutic effect of Cerebrolysin in acute
stroke and stroke rehabilitation (Gusev, 1994; Barolin, 1996; Haffner, 2001). In
our current trial the safety and efficacy of Cerebrolysin was assessed using a
randomised, controlled, double-blind study design.

Material and methods

Study design
This exploratory, multicentre, randomised, double-blind, placebo-controlled, parallel group study
was conducted at eight investigational sites in Austria, Czech Republic and Hungary, with 146
patients being enrolled in two groups: Cerebrolysin 50 mL (n ¼ 78) and placebo (n ¼ 68). The
study was conducted according to ICH-GCP guidelines as well as according to the Declaration
of Helsinki and the protocol was approved by local ethics review committees at all study sites.
Written informed consent was obtained for all patients before any study specific procedures were
carried out.
Seven evaluation visits were scheduled for the enrolled patients. Patients were screened for
study entry within 24 h of the onset of their stroke. Eligible patients were randomised to one of
418 G. Ladurner et al.

the two treatment groups and received the baseline evaluation of the efficacy outcome measures
(visit 1, day 0). Immediately following to the screening and baseline evaluation, patients were put
on study medication, once daily IV infusions of 50 mL Cerebrolysin or placebo for 21 consecutive
days. Further clinical efficacy and safety visits were scheduled on day 1 (visit 2), day 3 (visit 3),
day 7 (visit 4), day 14 (visit 5), at the end of the active treatment on day 21 (visit 6), and at day 90
(visit 7) post baseline.

Patient selection
Men and women suffering from their first acute ischaemic stroke with clinical symptoms of
middle cerebral artery area were enrolled in this study. Diagnostic procedures at study entry
included medical history, general physical examination, neurological examination, ECG, vital
signs, lab tests, and EEG. CT scans were performed to exclude patients with hemorrhagic stroke.
Further, the Canadian Neurological Scale (CNS) and the Glasgow Coma Scale (GCS) were rated
at screening. Patients were eligible if they were admitted to the hospital and received the first dose
of study medication within 24 h of the onset of the stroke and were between 45 and 85 years of
age at study entry. Patients were also required to have a GCS score of greater than 10 and a CNS
score between 4.5 to 8.0 at baseline. Patients with hemorrhagic strokes, transient ischaemic
attacks, patients with uncontrollable hypertension, acute myocardial infarction, congestive heart
failure, moderate to severe dementia prior to the stroke, coma or stupor, patients with other severe
concomitant diseases, patients with impaired renal function, and patients with a history of prior
stroke were excluded from the study. Concomitant use of nootropic drugs (e.g. piracetam), drugs
with dilatating effects on peripheral blood vessels (naftidrofuryl, cinnarizine, flunarizine, nimo-
dipine), as well as chronic intake of anti-depressants, tranquilizers, sedatives or CNS stimulatants
was prohibited throughout the study.

Treatment and randomization

Cerebrolysin 50 mL or placebo was administered once daily for 21 days by IV infusion in a
peripheral vein over a period of 20 minutes. In addition to the study treatment, both, the active
and the control group received Pentoxifylline (300 mg=day, IV) and Acetylsalicylic Acid
(250 mg=day, PO) for the first 21 days and Pentoxifylline (2
400 mg=day, PO) and Acetylsa-
licylic Acid (250 mg=day, PO) from day 22 to the end of the study at day 90.
The study medication was provided to the study centres by EBEWE Pharma in the form of a
ready-to-use infusion solution. The active medication contained 50 mL Cerebrolysin mixed with
50 mL of normal saline. Placebo contained 100 mL of normal saline. Both, active and control
medication were packaged in 100 mL amber glass vials and were indistinguishable in appearance.
Patients who met all entry criteria were assigned to the treatment groups in a 1:1 ratio, ac-
cording to a randomisation code generated by a computer software (EBEWE Pharma, Unterach,
Austria). The randomisation was carried out in blocks of 12 patients, stratified by study centre.
The investigators and all other study personnel were blind as to the random code assignment until
the completion of the statistical analysis. For each patient a sealed envelope with information on
the actual treatment dispensed was provided to the investigator for emergency cases. All enve-
lopes remained sealed throughout the study.

Efficacy assessments
The efficacy of Cerebrolysin was evaluated based on the neurological, the functional, and the cog-
nitive performance assessment of the patients. Efficacy measures were the Canadian Neurological
Scale (CNS) (Cot
e, 1986), the Barthel Index (BI) (Mahoney, 1965), the Glasgow Coma Scale
(GCS) (Teasdale, 1974), the Clinical Global Impression (CGI) (Guy, 1976), the Mini-Mental
State Examination (MMSE) (Folstein, 1975), the Syndrome Short Test (SST) (Erzigkeit, 1989),
the Self Assessment Scale (VonZerssen, 1970), and the Hamilton Rating Scale for Depression
(HAMD) (Hamilton, 1967). Efficacy evaluations were performed at Baseline and at all subse-
quent study visits on study days 1, 3, 7, 14, 21, and 90.
 Neuroprotection with Cerebrolysin in acute stroke 419

Safety measures
Adverse events (AEs), emergence of abnormal laboratory findings, changes in clinical laboratory
tests, as well as changes in vital signs and general physical and neurological examinations were
evaluated to determine the safety of Cerebrolysin. AEs were rated by the investigators as mild,
moderate or severe. The relationship to the study drug was rated using one of the following
categories: none, remote, possible, probable, or definite. These ratings were done under blinded
conditions. AEs were coded according to the COSTART dictionary.

Statistical analysis
An exploratory statistical analysis according to the intention-to-treat (ITT) principle with last-
observation-carried-forward (LOCF) was performed. The ITT population included all subjects
who were randomised, received at least one dose of study medication and provided baseline as
well as at least one post-baseline efficacy evaluation. Subgroup analyses of patients with right-
sided stroke, left-sided stroke, and patients who received the first dose of study medication within
6 h were also performed.
Comparability of the two groups with regard to demographic and background characteristics
was assessed using descriptive statistics and appropriate parametric and non-parametric statistical
tests.
Efficacy variables were analyzed using two-tailed statistics. Analyses were considered sig-
nificant if a p< 0.05 level was achieved. All efficacy scores at all study timepoints were evaluated
by descriptive statistics. For the comparison of differences between groups Student’s t-test for
unpaired data and the Wilcoxon-Mann-Whitney U-test were used. The Mantel-Haenszel Test was
used to assess differences between groups with respect to time x treatment interaction. For within
group comparison of baseline versus efficacy visit data, Student’s t-test for paired data and the
Wilcoxon signed rank test were used.
Since this was an exploratory study no sample size calculations have been performed. The
sample size has been chosen according to the clinical experience with Cerebrolysin in previous
studies.
All statistical analyses were carried out by Neumann and Team, Vienna, Austria, using a pro-
prietary statistical software which has been tested and validated according to current guidelines.

Results
Patient disposition
146 patients were randomised to two treatment groups and constituted the ITT
population: 78 patients to the Cerebrolysin group and 68 patients to the placebo
group. Of these patients, 67 of the Cerebrolysin group and 52 of the placebo
group completed the study. Reasons for the 25 cases of study discontinuation
were death (6 Cerebrolysin, 6 placebo), serious adverse event (1 placebo), and
consent withdrawn (3 Cerebrolysin; 9 placebo).

Demographic data and baseline disease characteristics

Baseline demographic and clinical characteristics of the patients are presented
in Table 1. No significant group differences of the demographic characteristics
were observed at baseline and the severity of the stroke at study entry was
comparable between the two groups. The average CNS score at baseline was
6.88 for the Cerebrolysin group compared to 6.68 for placebo patients. Like-
wise there was no difference in the GCS score, with baseline scores of 14.1 for
Cerebrolysin and 14.4 for placebo. The baseline data was in accordance with a
population of mild to moderate stroke patients.
420 G. Ladurner et al.

Table 1. Selected demographic data and baseline disease characteristics

Treatment

Cerebrolysin (n ¼ 78) Placebo (n ¼ 68)

Age (years)1 65  1.17 65  1.32

Gender (%)
Male 47 (60.3) 38 (55.9)
Female 31 (39.7) 30 (44.1)
Handedness (%)
Left 1 (1.3) 0 (0)
Right 77 (98.7) 68 (100)
Side of Stroke (%)
Left hemisphere 41 (52.6) 31 (45.6)
Right hemisphere 37 (47.4) 37 (54.4)
Duration of Symptoms (h)1 12.3  0.73 13.5  1.16
CNS1 6.88  0.09 6.68  0.14
GCS1 14.1  0.20 14.4  0.16
1
Values are means  SEM. No significant group differences were observed at baseline

The use of concomitant medications was homogeneously distributed

between the two groups. Most frequently used medications were agents ACE
inhibitors (Cerebrolysin 15% vs placebo 10%), cardiac therapy (11% vs 10%),
anti-diabetic drugs (13% vs 8%), calcium channel blockers (9% vs 10%) and
beta-blocking agents (10% vs 6%). There was no obvious difference between
the two groups as regards the type of concomitant medications used nor as
regards the frequency of concomitant drug intake.

Efficacy
The neurological outcome was assessed using the CNS score. Overall, no sig-
nificant differences between the two groups were observed (Fig. 1). In the CNS
subscore A1-Motor Functions, a strong tendency towards a significant Cere-
brolysin effect in comparison to placebo was seen in the full patient sample
(p<0.1). In contrast to the placebo group, the improvement from baseline to the
efficacy assessment visits revealed a significant benefit of the Cerebrolysin
group at day 1, 3, 7, 14, and 21 (p<0.05), and a trend for improvement at
the 3 months follow-up investigation (p<0.10) for the CNS section A1. The
neurological improvement of the patients after the stroke was generally faster in
the Cerebrolysin group as compared to placebo-treated patients. This was evi-
denced by the day 3 and 7 scores, which show the greatest difference between
the two groups. The lack of a significant effect at month 3 is most probably
caused by the reduced number of patients available for analysis at this time-
point (119 patients; 67 Cerebrolysin vs 52 Placebo).
No significant treatment differences have been picked up with the Glasgow
Coma Scale. The baseline scores for both groups (14.1 for Cerebrolysin and
14.4 for placebo) were very close to the maximum score for the GCS (15.0) and
 Neuroprotection with Cerebrolysin in acute stroke 421

Fig. 1. Time course of CNS section A1 score. Mean change from baseline in the CNS score of
the Cerebrolysin and placebo groups. Higher score differences correspond to better outcome.
The score difference in favour of Cerebrolysin did not reach the level significance. Most
pronounced effects were seen in the first 14 days after stroke onset

thus, no meaningful treatment effects could be detected with this instrument

due to a ceiling effect.
Promising results have been reported in the neuropsychological domain
(Fig. 2). In the syndrome short test (SST), which is less sensitive to disturbances

Fig. 2. Outcome and time course of the cognitive scores. Mean score difference between
Cerebrolysin and placebo groups in favour of Cerebrolysin-treated patients for the MMSE
and SST scores. SST scores showed a significant improvement of Cerebrolysin treated patients
versus placebo (p < 0.05; Mantel-Haenszel test; n ¼ 146). MMSE scores also favoured Cere-
brolysin treatment but were not significant. Note that greatest score differences in favour
Cerebrolysin were seen in the first days after the onset of the stroke for both scales, indicating
an accelerated recovery pattern for Cerebrolysin treated patients
422 G. Ladurner et al.

of speech than the MMSE, a significantly better performance of Cerebrolysin

patients as compared to placebo was evident (p<0.05; Mantel-Haenszel Test)
with a significant treatment effect in favour of Cerebrolysin for all study visits,
including the day 90 follow-up visit (p<0.05; t-test). The drug=placebo differ-
ence was most pronounced in the sub-group of patients with a stroke in the
right brain hemisphere (p<0.001; Mantel-Haenszel test). The difference in the
MMSE score did not reach statistical significance, however, a highly significant
effect of Cerebrolysin versus placebo was observed for the right-sided stroke
subgroup (p<0.001, Mantel-Haenszel test) for this instrument. This has been
confirmed by significant t-test results in favour of Cerebrolysin for days 1, 3,
and 14 after onset of the stroke, indicating an improvement of cognitive per-
formance of the stroke patients after treatment with Cerebrolysin. Both psycho-
metric test scores exhibited a time course similar to the neurological CNS score,
with an accelerated improvement pattern and greatest improvements during the
first days after the stroke for the patients in the Cerebrolysin group.
Activities of daily living were assessed with the Barthel Index. Cerebrolysin
treatment versus placebo did not reach the level of statistical significance. The
items stool incontinence and feeding of the Barthel Index, however, showed
significant superiority of Cerebrolysin versus Placebo (p<0.01 and p<0.05,
respectively). Overall, the baseline scores for the Barthel were indicative of a
very mild impairment of the patients in this study, when compared to patient
populations from other stroke trials (Fig. 3). This finding clearly has consider-
ably diminished the possibilities to detect a more clearcut treatment effect in the
patient population of this study due to the ceiling effect of the Barthel score.

Fig. 3. Outcome of the Barthel score at day 90 – comparison to the NINDS r-TPA study.
Percentage of patients in each of four categories (death, 0–50 points, 55–90 points, and 95–100
points) of Barthel Index outcome at day 90. The data is compared to the results of the NINDS
r-TPA study and indicates that patients in this study on average suffered from milder ischaemic
strokes. This is indicated by the lower number of patient deaths and the higher number of
patients with full recovery in our study as compared to the NINDS study population. Evidently,
a higher percentage of patients on Cerebrolysin achieved a full recovery compared to the
placebo group, but this difference did not reach statistical significance
 Neuroprotection with Cerebrolysin in acute stroke 423

Table 2. Patients with serious adverse events

Serious adverse event1 Treatment

Cerebrolysin (n ¼ 78) Placebo (n ¼ 68)

All SAEs (deaths) 6 (6) 7 (6)

Cerebral infarct (reinfarction) 4 (4) 2 (2)
Heart failure 2 (2) 1 (1)
Pulmonary embolism 0 (0) 2 (2)
Pneumonia 0 (0) 1 (1)
Hematemesis 0 (0) 1 (0)
1
Adverse events are encoded by Costart Adverse Reaction Terminology

No clinically important effects have been observed in the other outcome

measures used in this study, the Hamilton Depression scale, the Von-Zerssen
self-assessment questionnaire and the Clinical Global Impression. In the latter
scale, however, a significant treatment effect of Cerebrolysin was observed
in the subgroup of patients treated within six hours after the onset of stoke
(p<0.015; Mantel-Haenszel test), again with a time course of improvement
consistent with a pattern of accelerated recovery of patients on Cerebrolysin.

Safety
146 patients constituted the safety population with 78 patients receiving Cere-
brolysin and 68 receiving placebo. All patients who were randomised were
included in the safety analysis set.
The overall incidence of AEs was similar in both treatment groups, 16.4%
of Cerebrolysin patients as compared to 10.3% of placebo patients experienced
at least one AE. Thirteen patients (Table 2) reported a serious adverse event
(SAE), 6 in the Cerebrolysin group (7.69%) and 7 in the placebo group (8.82%).
With the exception of one SAE (hematemesis) in the placebo group which
was rated to be likely related to the study drug, there was no causal relation-
ship to the study drug for any other of the SAEs, as per the investigator’s assess-
ment. Twelve patients died during the study: 6 in the Cerebrolysin group (7.69%)
and 6 in placebo group (8.83%). None of the deaths was reportedly related to the
study drug administration.
Most AEs were rated mild in both treatment groups. AEs with an incidence
rate of greater 4% were hypertension, with 4 (5.1%) cases in the Cerebrolysin
group, and 4 (5.9%) cases in the placebo group, and constipation with 3 cases
in each group (3.8% vs 4.4% respectively). Overall, there was no significant
difference between the groups as regards the frequency or nature of adverse
events.
No clinically important difference between the two treatment groups for any
laboratory tests including haematology, blood chemistry, and urinalysis was
observed. Further, Cerebrolysin produced no clinically significant changes in
the vital signs. Overall, Cerebrolysin was well tolerated and no systemic pattern
of toxicity for Cerebrolysin was observed.
424 G. Ladurner et al.

Discussion
The history of neuroprotective treatment in ischaemic stroke started with the
use of barbiturates but side effects impeded their clinical development. Sub-
stantial effort has been spent since, in the clinical investigation of neuroprotec-
tive therapies that intervene at various stages of the ischaemic cascade. While
most of the substances tested demonstrated effectiveness in animal models, it
has been a major disappointment that most, if not all, substances tested to date
failed to show any meaningful results in the clinical field. This lead to the
assumption that the current design of stroke studies needs to be re-considered.
Neurotrophic factors have been used in treatment of stroke and have
achieved considerable results also in animal models but again, not in clinical
studies (FIBLAST Safety Study Group, 1998; Clark, 2000).
Cerebrolysin mimics the action of such neurotrophic factors and, in addi-
tion, has demonstrated a potent neuroprotective effect. Both has been proven
in vitro, in cell cultures, as well as in animal models of hypoxia and ischaemic
stroke (Gonzalez, 1998; Hartbauer, 2001; Hutter-Paier, 1996; Satou, 1994,
2000; Sugita, 1993; Veinbergs, 2000; Wronski, 2000; Frey, 2002; Tatebayashi,
2003). Clinically, Cerebrolysin is widely used for the treatment of Alzheimer’s
Disease and dementia in general (Ruether et al., 2001) and preliminary clin-
ical studies have suggested a therapeutic effect of Cerebrolysin in stroke pa-
tients (Gusev, 1994; Barolin, 1996; Haffner, 2001). In the present study we
tried to further explore the clinical effectiveness and usefulness of Cerebro-
lysin in ischaemic stroke with regard to neurological and cognitive function
recovery as well as with regard to the safety and tolerability profile of the
substance.
Overall, the results of our study did not show a significant effect of Cere-
brolysin in the CNS score. In the CNS section A1 – Motor weakness, there was
a significant difference in favour of Cerebrolysin until after the end of the active
treatment, but failed to demonstrate a significant effect on day 90, at the follow-up
visit. The rather small number of patients in our study, compared to other stroke
trials, certainly has impeded the possibility to observe clearcut treatment effect
of Cerebrolysin in the motor domain. Indeed, it must be emphasized that a
significant effect on the neurological score in our study would have been a
surprise, given the relatively low patient numbers and taking into account the
trial results for other neuroprotective compounds, which failed to produce any
meaningful treatment effects in neurological scores even with much larger
sample sizes.
Furthermore, the population in our study was characterised by a mild to a
very mild pattern of baseline impairment of the patients. This is clearly demon-
strated by our data for the Glasgow Coma Scale, where the average sore of the
two groups was close to the maximum test score for this scale. Evidently, such a
situation induces a pronounced ceiling effect, since patients cannot improve
beyond the maximum score, which thereby impedes a measurable treatment
effect for the test substance. This is certainly a limitation of our study and
it might be speculated that a more pronounced treatment effect would have
observed in a patient population with a more severe impairment at baseline.
 Neuroprotection with Cerebrolysin in acute stroke 425

The time window for inclusion in our study was 24 hours after the onset of
the stroke. This appears to be a wide window of opportunity when compared to
other studies with neuroprotective substances or with studies on thrombolytic
therapies. Since it is generally accepted that best results with neuroprotective
therapy can only be achieved with early intervention, ideally within the first few
hours after the stroke, the 24 h window in our study is a particularly challenging
factor when it comes to determination of efficacy. We have attempted to per-
form a subgroup analysis of patients enrolled within a 6 h time window, but the
extremely low number of patients in this sub-sample did not allow to draw
convincing conclusions. Nonetheless, it has provided some descriptive evidence
for increased efficacy especially in the global clinical outcome, and we spec-
ulate that earlier intervention with Cerebrolysin would have resulted in better
clinical outcome.
Despite the limitations associated with the small sample size, the mild base-
line impairment and the wide window of opportunity, significant effects of
Cerebrolysin on cognitive performance were observed in our study. Cognitive
function is not only important by itself for the functional restoration of the
individual itself, but is also an important predictor for the long-term rehabilita-
tion success. Most impressive results have been obtained with the SST, where a
significant effect of Cerebrolysin was demonstrated for the full patient sample
over the full study period of 90 days. The SST findings were complemented by
similar, although non-significant results with MMSE scale. However, there was
significant benefit of Cerebrolysin in the MMSE score in the right-sided
sub-group. The exact reason for this discrepancy in the results of two cognitive
measures remains elusive, we conclude, however, that the presence of aphasia
and speech problems in patients with left sided stroke has contributed to this
finding. The MMSE is certainly more sensitive to speech problems and in
addition with a maximum score of 30 also suffers from a pronounced ceiling
effect. It is thus not surprising that results obtained with the SST were more
conclusive. Interestingly, similar cognitive improvements after Cerebrolysin
therapy have extensively been demonstrated in patients with Alzheimer’s
Disease and also mixed and vascular dementia (Ruether et al., 2001).
The assessment of cognitive function improvement in stroke trials has
received little attention in the past, where studies have clearly concentrated
on the neurological and functional outcome. This has perhaps partly been due
to an underestimation of the importance of cognitive function as a predictor of
rehabilitation outcome for stroke patients. The finding of improvement of cog-
nitive function through Cerebrolysin therapy after stroke, however, could have
significant practical impact: it potentially increases the chances of successful
rehabilitation for the patients and probably reduces the risk of a mental decline
leading to post stroke dementia in some patients.
In summary, no significant improvements have been observed in the neu-
rological function measured by the CNS score. Cognitive outcomes, measured
with the SST, however, demonstrated a significant treatment effect of Cerebro-
lysin. The rather small sample size, the mild average severity of the stroke in
our patient population, the wide range in age distribution of the patients, as well
as the comparably wide window of opportunity may have impeded a better
426 G. Ladurner et al.

outcome. Nonetheless, our efficacy data together with the excellent safety record
suggests a potential beneficial effect of Cerebrolysin in acute ischaemic stroke
patients, in particular with respect to cognitive function outcome. In view of the
very limited beneficial effects that have been reported for other therapeutic
approaches for ischaemic stroke, like heparin or Aspirin (IST, 1997; CAST,
1997), the results of our study appear truly promising and warrant the further
investigation of Cerebrolysin in ischaemic stroke. Larger studies with a time
window for inclusion of six or even less hours and perhaps using more sensitive
outcome measures are needed to further confirm the efficacy of Cerebrolysin.
A combination therapy with Cerebrolysin and thrombolytic agents might
also be considered for the future clinical work. The restoration of blood flow
through thrombolysis together with early neuroprotection and neurotrophic sup-
port by Cerebrolysin might constitute a potent therapeutic approach to focal
cerebral ischaemia.

Appendix
The participants of the Cerebrolysin Study group were as follows: G. Ladurner, Christian-Doppler
Clinic, Salzburg, Austria; K. Niederkorn, University Hospital for Neurology, Graz, Austria; I.
Szirmai, Semmelweis University of Medicine, Budapest, Hungaria; P. Kalvach, Charles Univer-
sity, FNKV, Department of Neurology, Prague; F. Stockenhuber, Landeskrankenhaus, Oberpul-
lendorf, Austria; Z. Haffner, Petz Aladár Megyei K
orház, Gy€or, Hungaria; P. Ridzon, Thomayer’s
Hospital, Praha, Czech Republic; E. Diabl, Linz General Hospital, Linz, Austria.

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Authors’ address: Dr. G. Ladurner, Christian-Doppler Hospital, Ignaz-Harrer-Strasse 79, 5020

Salzburg, Austria, e-mail: g.ladurner@lks.at

Address for reprints: H. Moessler, EBEWE Pharma Ges.m.b.H. Nfg. KG, Mondseestrasse 11,
4866 Unterach, Austria, e-mail: herbert.moessler@ebewe.com