Read Efficacy and safety of Cerebrolysin in moderate to moderately severe Alzheimers disease: results of a randomized, doubleblind, controlled trial investigating three dosages of Cerebrolysin text version

European Journal of Neurology 2010

doi:10.1111/j.1468-1331.2010.03092.x

Efficacy and safety of Cerebrolysin in moderate to moderately severe AlzheimerÕs disease: results of a randomized, double-blind, controlled trial investigating three dosages of Cerebrolysin

X. A. Alvareza, R. Cacabelosa, C. Sampedroa, M. Aleixandreb, C. Linaresc, E. Granizoc, E. Dopplerd and H. Moesslerd

a

EuroEspes Biomedical Research Centre, Santa Maria de Babio, 15166 Bergondo, La Coruna; bFaculty of Psychology, Granada University,

Granada; cMemory Clinic, Malaga, Spain; and dEVER Neuro Pharma, formerly registered as EBEWE Neuro Pharma, Oberburgau 3, Austria

Keywords:

AlzheimerÕs disease, Cerebrolysin, randomized controlled trial

Received 3 July 2009 Accepted 9 March 2010

Background: Cerebrolysin is a neuropeptide preparation mimicking the effects of neurotrophic factors. This subgroup analysis assessed safety and efficacy of Cerebrolysin in patients with moderate to moderately severe AlzheimerÕs disease (AD) (ITT data set: N = 133; MMSE: 14­20) included in a dose-finding study (ITT data set: N = 251; MMSE: 14­25). Results of the mild AD subgroup (ITT data set: N = 118; MMSE: 21­25) are also presented. Methods: Patients with AD received 100 ml IV infusions of Cerebrolysin (10, 30 or 60 ml diluted in saline; N = 32, 34 and 35, respectively) or placebo (saline; N = 32) over twelve weeks (5 days per week for 4 weeks and 2 days per week for another 8 weeks). Primary efficacy criteria ADAS-cog+ (AlzheimerÕs Disease Assessment Scale Cognitive Subpart Modified) and CIBIC+ (Clinical Interview-based Impression of Change with Caregiver Input) were assessed 24 weeks after baseline. Results: At week 24, Cerebrolysin improved the global clinical function significantly with all three dosages and induced significant improvements in cognition, initiation of activities of daily living (ADL) and neuropsychiatric symptoms at 10-, 30- and 60-ml doses, respectively. Treatment effects on total ADL and other secondary parameters (MMSE, Trail-making test) were not significant. Cerebrolysin was safe and well tolerated. Conclusions: These results demonstrate the efficacy of Cerebrolysin in moderate to moderately severe AD, showing dose-specific effects similar to those reported for patients with mild to moderate AD. The benefits of Cerebrolysin in advanced AD need to be confirmed in larger trials.

Introduction

Cholinesterase inhibitors and memantine provide symptomatic relief to patients with AlzheimerÕs disease (AD), with no evidence of disease modification [1]. Both classes of compounds have positive effects on cognition and global clinical outcome, being less consistent with their benefits on behaviour and quality of life [2,3]. Priorities of current AD therapeutic research are to optimize symptomatic treatment, especially for moderately severe disease stages, and to develop disease´ Correspondence: X. Anton Alvarez, MD, PhD, EuroEspes Biomedical Research Centre, Santa Maria de Babio, 15166 Bergondo, La Coruna, Spain (tel.: +34 981 780505, fax +34 981 780511, e-mail: [email protected]).

modifying drugs [1,3]. Amyloid-based therapies and neurotrophic treatment are amongst the most promising alternatives for disease modification in AD [4,5]. As the number of trials in moderate to severe AD is quite limited, the evaluation of new drugs in this disease stage is highly recommendable [6]. Cerebrolysin is a neuropeptide preparation free of proteins, lipids and antigenic properties that contains 215.2 mg of low molecular weight peptides and free amino acids per millilitre. Cerebrolysin displays neurotrophic activity on dorsal root ganglia neurons [7] and rescues medial septal cholinergic neurons in a model of fimbria fornix transection after peripheral injection [8]. Neurotrophic-neuroprotective and procognitive effects of Cerebrolysin were also

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demonstrated in different animal models of AD [9­11]. Recent studies showed that Cerebrolysin reduces the production of amyloid-b in transgenic mice [12] and promotes neurogenesis [13,14]. Several randomized controlled clinical trials (RCTs) have evaluated the efficacy of Cerebrolysin in mild to moderate AD with positive results [15­20]. In a recent RCT performed with three doses of Cerebrolysin in mild to moderate AD, we found that in comparison with placebo Cerebrolysin improved global function, cognition and neuropsychiatric symptoms in a dosedependent manner [15]. Here we report for the first time on the safety and efficacy of three dosages of Cerebrolysin in the subgroup of patients with moderate [clinician's interview-based impression of severity (CIBIS)+ 3­4)] to moderately severe (CIBIS+ 5) AD enrolled in a larger RCT [15]. Although it was not included in the original statistical plan and the study was not powered to show differences between subgroups, data of the subgroup of patients with mild AD (MMSE: 21­25) were analysed and the results are presented.

Ethical aspects

Methods and patients

Study design

This clinical study was performed in compliance with Good Clinical Practice and the principles of the Declaration of Helsinki (1964) and subsequent revisions. Ethical approval for the study was granted by the ´ ´ ´ Comite Etico de Investigacion Cli´ nica de Galicia. The trial was registered at the Spanish Health Authorities registry (99­0120). Informed consent was given in writing by all patients and their caregivers. Co-authors HM and ED are employees of EBEWE Pharma. Both have no ownership in the company, and their compensation is not linked to the outcome of research projects. The EuroEspes Biomedical Centre and the authors did not receive from EBEWE Pharma any financial support for activities other than those directly related to the conduction and communication of research studies. No further commercial or other associations to disclose. This study was sponsored by EBEWE Pharma. Both the sponsor and the authors acted as guarantors of the study and had full access to the data. The sponsor was involved in development of study design, collection and interpretation of the data, in the writing of the report and in the decision to submit the manuscript for publication.

Efficacy measures

This 24-week, randomized, double-blind, placebo-controlled study was performed at one study site in Spain. Patients were randomly allocated to 10-, 30- or 60-ml Cerebrolysin or placebo in a 1:1:1:1 ratio. Patients received intravenous (IV) infusions of Cerebrolysin or placebo 5 days per week for 4 weeks and on 2 days per week in the following 8 weeks. Patient evaluations were performed at screening and baseline, during (Week 4) and after (Week 12) active treatment and 12 weeks thereafter (Week 24).

Patient population

Male and female outpatients of >50 years were eligible for study participation if they had a diagnosis of probable AD [21]. Inclusion criteria included a MiniMental State Examination (MMSE) [22] score of 14­25 (patients with a MMSE score at baseline of 14­20, both inclusive, were selected for the subgroup analysis), a Modified Hachinski Ischaemia Scale [23] score of £4, a Hamilton Depression Scale [24] score of £15, a computer tomography (CT) or magnetic resonance imaging (MRI) consistent with the diagnosis of probable AD, good general health without clinically significant laboratory abnormalities or other diseases expected to interfere with the study. Exclusion criteria as specified in the previous publication [15] were the usual for this kind of clinical trials.

Primary efficacy measures were the AlzheimerÕs Disease Assessment Scale Cognitive Subpart Modified (ADAScog+) score [25] change from baseline to Week 24 and the CIBIC+ score [26] at Week 24. Secondary efficacy measures were changes from baseline to Week 4, 12 and 24 in MMSE, ADAS-cog [27], Neuropsychiatric Inventory (NPI) [28], Disability Assessment in Dementia (DAD) [29] and Trail-making Test (Trails-A) [30] scores. Responder rates were assessed for ADAScog+ (responder: improvement of 4 points relative to baseline) and CIBIC+ (responder: score £3; corresponding to improvement).

Safety measures

Adverse events (AEs) and vital signs were monitored during the study. Laboratory parameters were assessed at baseline, Week 12 and Week 24. Physical and neurological examinations were evaluated at baseline, Week 4, 12 and 24.

Statistical analysis

Efficacy analyses are based on the Intention-to-Treat (ITT) patient population, which includes all randomized patients who had a baseline MMSE score of £20,

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received at least one dose of study medication and had baseline and at least one post-baseline assessment of both primary end-points. In case of missing data, the last-observation-carried-forward (LOCF) method was applied. Comparability of the groups at baseline was assessed using descriptive statistics and appropriate parametric and non-parametric statistical tests. Efficacy variables were analysed using two-tailed statistics. Analyses were considered significant if a probability level of P < 0.05 was achieved. CIBIC+ score was analysed by Cochran-Mantel-Haenszel (CMH); ADAScog+ and secondary outcome measures were subjected to analysis of covariance (ANCOVA) using baseline score as a covariate. Responder rates were analysed using logistic regression, and odds ratios for achieving a response to treatment and the 95% CI were estimated. Exactly the same analyses were conducted in the subgroup of patients with baseline MMSE score 21. For safety analysis, treatment groups were compared with respect to incidence rates of AEs, changes in vital signs, laboratory abnormalities, physical and neurological examination findings and weight changes.

qualified for subgroup analysis (ITT:MMSE £ 20). Patient numbers and reasons for discontinuation are given in Fig. 1. The mild AD subgroup was integrated by 118 patients (ITT:MMSE 21­25).

Demographic data and baseline disease characteristics

No significant group differences were observed at baseline (Table 1). Mean disease duration at baseline was 4.6 ± 0.23 years. Treatment groups were comparable for cognitive performance and global clinical impression and were in accordance with a population suffering from moderate to moderately severe AD. The use of concomitant medication was similar in all treatment groups. The same applies for patients with mild AD (Table 2).

Efficacy

Results

Patient disposition

Of 279 patients randomized, 251 patients were included in the total ITT analysis set and of these 133 patients

Cerebrolysin 10-ml, but not 30- and 60-ml, was effective in improving cognitive performance as assessed by ADAS-cog+ with a significant treatment difference compared to placebo at Week 24 (Table 3, Fig. 2). This improvement was confirmed by a responder rate of 37.5% versus 12.5% in the placebo group. The odds ratios for achieving response in ADAS-cog+ were significant with 10-ml (4.20; 95% CI: 1.18/14.93; P = 0.026) and 30-ml doses (3.82; 95% CI: 1.08/13.48; P = 0.037), but not with the dose of 60-ml (2.80; 95%

Randomized N = 279

Cerebrolysin 10 ml N = 69 Received no medication (N = 5) No post-baseline data (N = 4) ITT Population N = 60

Cerebrolysin 30 ml N = 70 Received no medication (N = 1) No post-baseline data (N = 4) ITT Population N = 65

Cerebrolysin 60 ml N = 71 No post-baseline data (N = 3)

Placebo N = 69 Received no medication (N = 4) No post-baseline data (N = 7) ITT Population N = 58

ITT Population N = 68

ITT: MMSE 20 N = 133

ITT Population N = 251

Cerebrolysin 10 ml N = 32 Total discontinued N=1 Adverse event (N = 1)

Cerebrolysin 30 ml N = 34 Total discontinued N=3 Noncompliance (N = 1) Consent withdrawn (N = 1) Other reasons (N = 1) Completed study N = 31

Cerebrolysin 60 ml N = 35 Total discontinued N=2 Noncompliance (N = 1) Consent withdrawn (N = 1)

Placebo N = 32 Total discontinued N=4 Noncompliance (N = 1) Consent withdrawn (N = 2) Other reasons (N = 1) Completed study N = 28

Completed study N = 31

Completed study N = 33

Figure 1 Enrolment and disposition of all patients participating in the clinical study (ITT data set) and of patients having an MMSE score of £20 at baseline (ITT:MMSE £ 20 data set). ITT, intention to treat; MMSE, Mini-Mental State Examination.

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Cerebrolysin 10 ml (n = 32) Gender Male Female Age (years) Disease duration (years) MMSE Mean ± SE ADAS-cog+ Mean ± SE CIBIS+ Mildly ill (3) Moderately ill (4) Markedly ill (5) 30 ml (n = 34) 60 ml (n = 35) Placebo (n = 32)

Table 1 Selected demographic data and baseline disease characteristics

5 (15.6) 27 (84.4) 72.4 ± 1.98 4.3 ± 0.41 16.4 ± 0.4 49.7 ± 2.4 1 (3.1) 20 (62.5) 11 (34.4)

7 (20.6) 27 (79.4) 75.1 ± 1.54 4.2 ± 0.39 17.0 ± 0.3 43.5 ± 2.0 1 (2.9) 27 (79.4) 6 (17.6)

9 (25.7) 26 (74.3) 75.3 ± 1.25 4.3 ± 0.47 16.3 ± 0.3 45.1 ± 2.0 3 (8.6) 24 (68.6) 8 (22.9)

8 (25.0) 24 (75.0) 77.0 ± 1.63 5.7 ± 0.53 16.8 ± 0.4 44.4 ± 2.2 1 (3.1) 20 (62.5) 11 (34.4)

Values are n (%) for gender and CIBIS+ score and mean ± standard error for age and disease duration; ITT:MMSE £ 20 data set.

Cerebrolysin 10 ml (n = 28) Gender Male Female Age (years) Disease duration (years) MMSE Mean ± SE Range ADAS-cog+ Mean ± SE Range CIBIS+ Mildly ill (3) Moderately ill (4) Markedly ill (5) 30 ml (n = 31) 60 ml (n = 33) Placebo (n = 26)

Table 2 Selected demographic data and baseline disease characteristics

12 (42.9) 16 (57.1) 72.0 ± 1.59 4.4 ± 0.66 23.4 ± 0.3 21­25 25.0 ± 1.8 11­49 18 (64.3) 10 (35.7) 0 (0.0)

9 (29.0) 22 (71.0) 71.5 ± 1.44 3.5 ± 0.40 22.7 ± 0.2 21­25 28.3 ± 1.7 12­50 19 (61.3) 12 (38.7) 0 (0.0)

11 (33.3) 22 (66.7) 73.9 ± 1.25 3.3 ± 0.37 23.2 ± 0.2 21­25 25.1 ± 1.4 10­47 23 (69.7) 10 (30.3) 0 (0.0)

12 (46.2) 14 (53.8) 70.1 ± 1.86 4.0 ± 0.49 23.4 ± 0.3 21­25 22.6 ± 1.4 12­35 16 (61.5) 10 (38.5) 0 (0.0)

Values are n (%) for gender and CIBIS+ score and mean ± standard error for age and disease duration; ITT:MMSE 21­25 data set.

CI: 0.78/10.06; P = 0.114). In the subgroup of patients with mild AD, Cerebrolysin enhanced the cognitive performance with respect to baseline at all doses tested, but no significant treatment effects were demonstrated (Table 4). In the CIBIC+, all Cerebrolysin dosages improved global clinical function significantly in comparison with placebo. Best treatment effects were obtained with 10-ml Cerebrolysin, followed by 30-ml and 60-ml dosages. CIBIC+ responder analysis confirmed results of CIBIC+ score analysis (Table 3). Odds ratios for the proportion of patients achieving a CIBIC+ response were significant for all Cerebrolysin doses (Table 3).

Cerebrolysin also improved global functioning significantly with all doses in mild AD (Table 4), but the odds ratios for achieving a CIBIC+ response were clearly lower than in moderate to moderately severe AD, which is consistent with the different rate of CIBIC+ responders observed in both subgroups for patients on placebo (Tables 3 and 4). Analysis of the secondary efficacy criteria provided supportive evidence for the efficacy of Cerebrolysin. In activities of daily living as assessed by DAD, Cerebrolysin-treated patients performed better than those on placebo but failed to reach the level of statistical significance (Table 3). Analyses of DAD subscores

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Table 3 Summary of efficacy statistics at Week 24 for the ITT:MMSE £ 20 population Baseline score ADAS-cog+ Placebo 10-ml Cere 30-ml Cere 60-ml Cere Disability Assessment Placebo 10-ml Cere 30-ml Cere 60-ml Cere NPI Placebo 10-ml Cere 30-ml Cere 60-ml Cere CIBIC+ Placebo 10-ml Cere 30-ml Cere 60-ml Cere

a

LS mean change ± SE

Treatment differencea

95% CI

P-value

44.36 49.73 43.48 45.09 in Dementia 52.59 50.42 62.47 59.15 13.6 18.2 10.8 13.5 Score ± SD 5.06 3.34 3.41 3.66 ± ± ± ± 0.34 1.82 0.44 1.49

4.538 ± 1.853 )1.838 ± 1.876 0.007 ± 1.802 1.672 ± 1.770 )6.20 ± 3.00 )3.26 ± 3.02 1.46 ± 2.93 )5.08 ± 2.87 2.5 ± 2.1 )0.9 ± 2.2 )3.1 ± 2.1 )3.7 ± 2.0 Responders (%)b 9.4 59.4 55.9 45.7

)6.376 )4.531 )2.866

)12.665/)0.087 )10.659/1.596 )8.950/3.219

0.046 0.195 0.541

2.94 7.65 1.12

)5.45/11.33 )0.69/16.00 )7.12/9.36

0.488 0.072 0.789

)3.4 )5.6 )6.2 Odds ratioc

)9.4/2.6 )11.5/0.3 )12.0/)0.3 95% CI

0.264 0.063 0.039 P-value

14.13 12.24 8.14

3.55/56.28 3.12/48.09 2.08/31.78

0.0002 0.0003 0.0026

For ADAS-cog+ and NPI negative treatment differences indicate a favourable effect of Cerebrolysin compared to placebo; bCIBIC+ responders are defined as having a score £3; cOdds ratios are for Cerebrolysin versus placebo. N = 32 for 10-ml Cerebrolysin (Cere), N = 34 for 30-ml Cere, N = 35 for 60-ml Cere, N = 32 for placebo.

showed at all study visits significant superiority of 30-ml Cerebrolysin over placebo in ÔInitiationÕ with the highest estimated treatment difference of 11.65 points (95% CI: 2.10/21.21; P = 0.017) at Week 24 (Table 5). Cerebrolysin was descriptively superior to placebo in improving neuropsychiatric disturbances as measured by NPI, but significant treatment differences were only observed with the 60-ml dosage (Table 3, Fig. 3). For the other secondary outcome measures, the MMSE and

the Trails-A, Cerebrolysin-treated patients showed numerically but not statistically better results than patients on placebo. Results obtained in the subgroup of patients with mild AD are in line with those observed in moderate to moderately severe AD, although no significant treatment effects were found. Patients treated with Cerebrolysin showed descriptively better performance in activities of daily living than those on placebo (Table 4); and particularly in instrumental

ADAS­cog+ score LS mean change from baseline

­5 ­4 ­3 ­2 ­1 0 1 2 3 4 Active treatment 5 0 4 8 12 16 P=0.048 P=0.011

Placebo Cerebrolysin 10 ml Cerebrolysin 30 ml Cerebrolysin 60 ml P=0.046

Figure 2 Time course of the ADAScog+: LS mean change from baseline. ITT:MMSE £ 20 analysis, n = 32 for 10-ml, n = 34 for 30-ml, n = 35 for 60-ml Cerebrolysin and n = 32 for placebo. Negative score differences indicate improvement. Exact P-values for comparison to placebo are given for 10-ml (Week 12, Week 24) and 30-ml (Week 4) Cerebrolysin dose groups.

20

24

Study week

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Table 4 Summary of efficacy statistics at Week 24 for the ITT:MMSE 21-25 population Baseline score ADAS-cog+ Placebo 10-ml Cere 30-ml Cere 60-ml Cere Disability Assessment Placebo 10-ml Cere 30-ml Cere 60-ml Cere NPI Placebo 10-ml Cere 30-ml Cere 60-ml Cere CIBIC+ Placebo 10-ml Cere 30-ml Cere 60-ml Cere

a

LS mean change ± SE )0.753 )1.840 )2.557 )1.994 0.06 1.97 1.04 1.18 )1.9 )2.4 )1.5 )6.0

Treatment differencea

95% CI

P-value

22.62 24.96 28.27 25.12 in Dementia 79.01 79.19 83.41 76.38 12.5 12.7 10.1 12.8 Score ± SD 4.23 2.89 3.06 2.94 ± ± ± ± 1.31 1.42 1.18 0.83

± ± ± ±

1.382 1.317 1.271 1.213

)1.087 )1.804 )1.241

)5.60/3.432 )6.316/2.708 )5.597/3.115

0.888 0.650 0.831

± ± ± ±

2.05 1.98 1.89 1.83

1.90 0.98 1.12

)3.74/7.55 )4.55/6.50 )4.33/6.56

0.506 0.727 0.686

± ± ± ±

1.6 1.6 1.5 1.5

)0.6 0.3 )4.1 Odds ratioc

)5.1/3.9 )4.1/4.8 )8.4/0.2 95% CI

0.805 0.876 0.064 P-value

Responders (%)b 34.6 71.4 64.5 72.7

4.72 3.43 5.04

1.49/14.93 1.15/10.24 1.65/15.34

0.008 0.027 0.004

For ADAS-cog+ and NPI negative treatment differences indicate a favourable effect of Cerebrolysin compared to placebo; bCIBIC+ responders are defined as having a score £3; cOdds ratios are for Cerebrolysin versus placebo. N = 28 for 10-ml Cerebrolysin (Cere), N = 31 for 30-ml Cere, N = 33 for 60-ml Cere, N = 26 for placebo.

Baseline Basic activities Placebo 77.02 ± 10-ml Cere 72.61 ± 30-ml Cere 82.50 ± 60-ml Cere 79.66 ± Instrumental activities Placebo 34.39 ± 10-ml Cere 33.18 ± 30-ml Cere 47.19 ± 60-ml Cere 43.88 ± Initiation Placebo 57.43 ± 10-ml Cere 54.32 ± 30-ml Cere 66.01 ± 60-ml Cere 63.25 ± Planning and Organization Placebo 42.97 ± 10-ml Cere 41.29 ± 30-ml Cere 50.08 ± 60-ml Cere 48.44 ± Effective performance Placebo 55.21 ± 10-ml Cere 53.68 ± 30-ml Cere 68.09 ± 60-ml Cere 63.17 ±

Week 4 )4.13 ± 2.37 0.08 ± 2.38 2.11 ± 2.30 )2.83 ± 2.26 )2.43 ± 2.06 0.23 ± 2.06 1.42 ± 2.01 0.32 ± 1.96 )4.56 ± 2.46 1.07 ± 2.48 4.05 ± 2.40 )2.86 ± 2.36 )2.49 ± 2.16 0.15 ± 2.16 2.66 ± 2.10 )0.04 ± 2.06 )2.36 )0.74 )0.15 )0.03 ± ± ± ± 2.20 2.20 2.15 2.09

Week 12 )4.76 ± 3.18 )0.29 ± 3.20 2.93 ± 3.10 )4.07 ± 3.04 )2.38 ± 2.22 0.58 ± 2.22 3.29 ± 2.16 )1.87 ± 2.12 )3.63 ± 2.82 1.49 ± 2.83 6.41 ± 2.75 )5.01 ± 2.70 )2.58 ± 2.62 0.91 ± 2.63 3.51 ± 2.55 )1.60 ± 2.51 )3.68 ± 2.57 )1.21 ± 2.58 0.35 ± 2.51 )1.65 ± 2.45

Week 24 )7.96 ± 3.98 )5.81 ± 4.00 0.13 ± 3.88 )5.97 ± 3.81 )5.06 ± 2.81 )1.64 ± 2.81 2.59 ± 2.73 )4.41 ± 2.68 )7.97 ± 3.45 )2.89 ± 3.47 3.68 ± 3.36 )7.37 ± 3.30 )6.19 ± 3.45 )2.86 ± 3.46 2.43 ± 3.35 )3.75 ± 3.30 )5.02 )4.32 )0.54 )3.91 ± ± ± ± 3.12 3.13 3.05 2.97

Table 5 Disability Assessment in Dementia (DAD) subscores changes from baseline for the ITT:MMSE £ 20 population

4.01 5.13 3.83 4.25 5.47 4.75 4.69 4.15 4.49 4.77 4.19 4.44 4.83 5.21 4.78 4.15 4.68 4.44 3.84 3.92

Values are mean ± SE for baseline and LS mean ± SE for Week 4, 12 and 24. Negative DAD scores indicate deterioration. N = 32 for 10-ml Cerebrolysin (Cere), N = 34 for 30-ml Cere, N = 35 for 60-ml Cere, N = 32 for placebo.

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NPI Score LS mean change from baseline

­6 ­5 ­4 ­3 ­2 ­ 1 0 1 2 Active treatment 3 0 4 8

P<0.05

Placebo Cerebrolysin 10 ml Cerebrolysin 30 ml Cerebrolysin 60 ml P<0.05

Figure 3 Time course of the NPI: LS mean change from baseline. ITT:MMSE £ 20 analysis, n = 32 for 10-ml, n = 34 for 30-ml, n = 35 for 60-ml Cerebrolysin and n = 32 for placebo. Negative score differences indicate improvement. Exact P-values for comparison to placebo are given for the Cerebrolysin 30 ml (Week 12) and Cerebrolysin 60 ml (Week 24) dose groups.

12 Study week

16

20

24

activities, effective performance and initiation subscores with the 10-ml dose (Table 6). Cerebrolysin 60-ml induced a borderline significant improvement in behaviour when compared to placebo ()4.1; 95% CI: )8.4/ 0.2; P = 0.064) (Table 4).

Safety

All 133 patients of the ITT:MMSE £ 20 subgroup were included in the safety population. The incidence of

Table 6 Disability Assessment in Dementia (DAD) subscores changes from baseline for the ITT:MMSE 21-25 population

adverse events did not show group differences. At least one AE was experienced by 56.3% of patients on 10-ml Cerebrolysin, 47.1% of patients on 30-ml, 62.9% of patients on 60-ml and 62.5% of patients on placebo. The Costart Body Systems with the highest incidence rate were ÔNervous SystemÕ with 34 events, ÔBody as a WholeÕ with 23 events and ÔUrogenital SystemÕ with 22 events. The most common AEs with an incidence rate of >10% were depression and fever, each affecting 12.5% of patients in the 10-ml group, and urinary tract

Baseline Basic activities Placebo 88.46 ± 10-ml Cere 91.81 ± 30-ml Cere 95.05 ± 60-ml Cere 88.50 ± Instrumental activities Placebo 71.62 ± 10-ml Cere 69.70 ± 30-ml Cere 74.33 ± 60-ml Cere 66.98 ± Initiation Placebo 78.53 ± 10-ml Cere 78.55 ± 30-ml Cere 84.41 ± 60-ml Cere 76.94 ± Planning and Organization Placebo 73.20 ± 10-ml Cere 74.29 ± 30-ml Cere 79.58 ± 60-ml Cere 66.05 ± Effective performance Placebo 83.26 ± 10-ml Cere 83.02 ± 30-ml Cere 85.32 ± 60-ml Cere 82.95 ±

Week 4

Week 12

Week 24 )0.52 ± 2.12 0.30 ± 2.04 )0.08 ± 1.95 )1.52 ± 1.88 0.56 3.21 2.18 3.03 1.61 4.47 1.59 2.29 ± ± ± ± ± ± ± ± 2.70 2.61 2.48 2.41 2.52 2.43 2.32 2.24

3.83 2.83 2.72 2.92 5.65 5.65 4.99 4.51 4.95 4.27 3.56 3.80 5.80 5.52 4.34 4.72 4.20 3.90 3.68 3.61

0.04 0.69 0.88 0.20 1.43 3.20 2.18 2.02 0.72 2.89 2.03 0.56

± ± ± ± ± ± ± ± ± ± ± ±

0.88 0.85 0.81 0.78 1.63 1.57 1.50 1.45 1.98 1.91 1.82 1.76

0.65 ± 1.32 1.13 ± 1.27 0.03 ± 1.21 )0.02 ± 1.17 1.95 5.38 3.07 3.44 2.56 4.25 1.84 2.48 1.28 1.71 0.09 3.05 0.58 4.25 2.68 1.30 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 2.31 2.22 2.12 2.05 2.00 1.93 1.85 1.78 2.00 1.93 1.85 1.79 1.65 1.59 1.51 1.46

1.60 ± 1.58 0.75 ± 1.52 )0.17 ± 1.46 2.50 ± 1.41 0.32 2.43 2.73 1.24 ± ± ± ± 1.12 1.08 1.03 1.00

)0.39 ± 2.43 )0.53 ± 2.34 0.00 ± 2.24 1.67 ± 2.18 )0.91 ± 2.04 1.60 ± 1.97 1.50 ± 1.87 )0.01 ± 1.81

Values are mean ± SE for baseline and LS mean ± SE for Week 4, 12 and 24. Negative DAD scores indicate deterioration. N = 28 for 10-ml Cerebrolysin (Cere), N = 31 for 30-ml Cere, N = 33 for 60-ml Cere, N = 26 for placebo.

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infection with 12.5% in the 10-ml group, 20.0% in the 60-ml group and 25.0% in the placebo group. Four patients reported serious adverse events, two in the 10-ml group and one each in the 30-ml and placebo groups. None of these cases was causally related to the study drug. No case of death was reported in this population. Safety evaluation of Cerebrolysin did not show any safety issue when used in doses up to 60 ml in patients with moderate to moderately severe AD.

Discussion

Results of this study demonstrate significant improvements in cognitive performance and global clinical function in patients with moderate to moderately severe AD after treatment with 10-ml Cerebrolysin. Results of behaviour and activities of daily living were descriptively but not statistically in favour of 10-ml Cerebrolysin when compared to placebo (Table 3). Similar positive trends were observed in mild AD with 10-ml Cerebrolysin, which significantly improved global functioning only (Table 4). Almost similar treatment effects were observed with the 30-ml Cerebrolysin dose, enhancing global clinical function and the probability of achieving an ADAScog+ response significantly with respect to placebo. Marginal significant improvements were reported for behaviour and activities of daily living (Tables 3 and 4, Fig. 3). A significant treatment effect of 30-ml Cerebrolysin was observed in the DAD subscore ÔinitiationÕ, which indicates that patients are more active and prone to perform activities of daily living. Altogether, these results suggest that 30-ml Cerebrolysin might also be effective for the treatment of patients with moderate to moderately severe AD. In the subgroup of patients with mild AD, Cerebrolysin 30 ml improved the global clinical function significantly and induced descriptively higher effects on cognition and activities of daily living when compared to placebo (Table 4). Treatment with 60-ml Cerebrolysin resulted in significant improvements in global function and neuropsychiatric symptoms, with no significant effects on cognitive performance and activities of daily living. Mild favourable treatment differences observed for cognition and activities of daily living, together with the significant reduction of behavioural disturbances might account for the significant results of this Cerebrolysin dose in the global clinical evaluation. Almost similar results were observed with this dose of Cerebrolysin in patients with mild AD (Table 4). In summary, efficacy results of this study indicate a somewhat dose-specific response to Cerebrolysin with dosages of 10­30 ml to improve cognition and the initiation of daily living activities and dosages of

30­60 ml to improve behaviour in patients with moderate to moderately severe AD. Basically the same dissociated response was observed with low and high doses of Cerebrolysin in mild AD. Global clinical function was improved by all Cerebrolysin dosages. The improvements in CIBIC+ evaluations, even besides significant effects in particular domains, seem to reflect the positive influence of Cerebrolysin on some key clinical aspects frequently observed/reported by clinicians and caregivers like alertness, general activity and motivation. According to the clinical interview-based impression, after treatment with Cerebrolysin, patients were more reactive and communicative, showed a higher involvement in social interactions and daily activities, and appeared more tranquil, self-confident and with an enhanced well-being feeling. These observations are consistent with significant and/or relative improvements detected in cognition and activities of daily living (initiation, effective performance and instrumental activities), as well as with significant reductions in NPI symptoms like irritability, agitation, depression and apathy (data not shown). According to the present results, cognitive benefits of Cerebrolysin are more pronounced in moderate to moderately severe than in mild patients. This difference seems to be mainly owing to the cognitive decline exhibited by moderate to moderately severe patients on placebo, which was absent in mild AD. Similar observations were reported for 30-ml Cerebrolysin [18] and for rivastigmine [31]. The effect size of Cerebrolysin in the cognitive domain in moderate to moderately severe AD is comparable to that reported for cholinesterase inhibitors and memantine [2,3,32]. Current and previous data [15­18] show that Cerebrolysin improves global function and cognition to the same extent as cholinesterase inhibitors [3,33­35]. The positive effects of Cerebrolysin were substantially similar at the end of the treatment period (Week 12) and twelve weeks later (Week 24). This is in agreement with reports of persisting efficacy for several months after stopping Cerebrolysin treatment [15,17,18] and is in contrast to the loss of efficacy of cholinesterase inhibitors within 6 weeks [36]. Long-term cognitive effects of Cerebrolysin are also in good agreement with a putative neurotrophic mode of action and with its long-lasting influence on behaviour, dendritic arbourization and synaptogenesis [10,11]. The reduction of brain amyloid deposition and inflammation and the stimulation of neurogenesis demonstrated in experimental studies might also contribute to the clinical benefits of Cerebrolysin [9,12­14]. Although the neurotrophic-neuroprotective actions of Cerebrolysin may account for its behavioural effects in patients with AD, the discrepancy of doses

Ó 2010 The Author(s) Journal compilation Ó 2010 EFNS European Journal of Neurology

Cerebrolysin in moderate to moderately severe AlzheimerÕs disease

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improving cognition (10­30 ml) and behaviour (60 ml) suggests the involvement of different mechanisms. In this regard, we recently found that 60-ml Cerebrolysin reduced serum tumour necrosis factor alpha (TNF-a) levels with respect to placebo in AD [37]. This finding together with evidence of increased TNF-a in psychiatric disorders and its reduction after successful treatment [38,39] suggests that changes in TNF-a might be relevant for the effects of Cerebrolysin on behaviour. Safety results indicate that dosages of up to 60-ml Cerebrolysin are safe and well tolerated in patients with moderate to moderately severe AD. No differences with respect to placebo were found for the incidences of adverse events, changes on laboratory parameters, vital signs, physical and neurological examinations, or the use of concomitant medications for any of the Cerebrolysin doses evaluated. This subgroup analysis indicates that Cerebrolysin is effective at the 10-ml dose for the treatment of patients with moderate to moderately severe AD. A stabilizing effect of Cerebrolysin in these AD stages is suggested by the persistence of its therapeutic benefits 3 months after stopping treatment. These positive results of Cerebrolysin have to be confirmed in larger RCTs.

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Ó 2010 The Author(s) Journal compilation Ó 2010 EFNS European Journal of Neurology

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Efficacy and safety of Cerebrolysin in moderate to moderately severe Alzheimers disease: results of a randomized, doubleblind, controlled trial investigating three dosages of Cerebrolysin

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Efficacy and safety of Cerebrolysin in moderate to moderately severe Alzheimers disease: results of a randomized, doubleblind, controlled trial investigating three dosages of Cerebrolysin