Major Clinical Trial. Cerebrolysin in Patients With Acute Ischemic Stroke in Asia Results of a Double-Blind, Placebo-Controlled Randomized Trial

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1 Major Clinical Trial Cerebrolysin in Patients With Acute Ischemic Stroke in Asia Results of a Double-Blind, Placebo-Controlled Randomized Trial Wolf-Dieter Heiss, MD*; Michael Brainin, MD; Natan M. Bornstein, MD; Jaakko Tuomilehto, MD, MPolSc, PhD; Zhen Hong, MD*; for the Cerebrolysin Acute Stroke Treatment in Asia (CASTA) Investigators Background and Purpose Cerebrolysin showed neuroprotective and neurotrophic properties in various preclinical models of ischemia and small clinical trials. The aim of this large double-blind, placebo-controlled randomized clinical trial was to test its efficacy and safety in patients with acute ischemic stroke. Methods Patients with acute ischemic hemispheric stroke were randomized within 12 hours of symptoms onset to active treatment (30 ml Cerebrolysin daily) or placebo (saline solution) given as intravenous infusion for 10 days in addition to aspirin (100 mg daily). The patients were followed up to 90 days. The primary end point was the result of a combined global directional test of modified Rankin Scale, Barthel Index, and National Institutes of Health Stroke Scale. Adverse events were documented to assess safety. Results A total of 1070 patients were enrolled in this study. Five hundred twenty-nine patients were assigned to Cerebrolysin and 541 to placebo. The confirmatory end point showed no significant difference between the treatment groups. When stratified by severity however, a post hoc analysis of National Institutes of Health Stroke Scale and modified Rankin Scale showed a trend in favor of Cerebrolysin in patients with National Institutes of Health Stroke Scale 12 (National Institutes of Health Stroke Scale: OR, 1.27; CI lower bound, 0.97; modified Rankin Scale: OR, 1.27; CI lower bound, 0.90). In this subgroup, the cumulative mortality by 90 days was 20.2% in the placebo and 10.5% in the Cerebrolysin group (hazard ratio, ; CI lower bound, ). Conclusions In this study, the confirmatory end point showed neutral results between the treatment groups. However, a favorable outcome trend was seen in the severely affected patients with ischemic stroke treated with Cerebrolysin. This observation should be confirmed by a further clinical trial. Clinical Trial Registration URL: Unique identifier: NCT (Stroke. 2012;43: ) Key Words: acute ischemic stroke Cerebrolysin clinical trial neuroprotectants stroke severity Treatment of acute ischemic stroke is still based on thrombolytic therapy and additional treatments have up to now not been proven to be effective. 1,2 To help investigate further potential treatments, the Stroke Therapy Academic Industry Roundtable (STAIR) has recommended criteria that should be applied for preclinical and clinical evaluation of acute ischemic stroke therapies. A major interest within these recommendations is to optimize the translation from animal models to clinical trials. 3,4 Cerebrolysin is a porcine brain-derived preparation of lowmolecular-weight neuropeptides (10 kda) and free amino acids that shows pharmacodynamic properties similar to those of naturally occurring neurotrophic factors. 5,6 Previous encouraging results have been observed in cell and organ culture studies 7 9 as well as in animal stroke models and in smaller clinical trials in acute ischemic stroke. There is indication that Cerebrolysin is able to prevent acute neuronal damage by preventing cell death, free radical formation and inflammation, and by counteracting excitotoxicity and that it can also improve and accelerate the recovery of neurological function In vivo data showed that Cerebrolysin substantially improved neurological outcome and augmented neurogenesis in the ischemic brain in rodents In accordance with the STAIR criteria and based on previous data, a large Received June 21, 2011; final revision received November 9, 2011; accepted November 30, Miguel Perez-Pinzon, PhD, was the Guest Editor for this paper. From the Max-Planck Institut für Neurologie (W.-D.H.), Koeln, Germany; the Department of Clinical Neurosciences (M.B.), Donau-Universität Krems, Krems, Austria; Tel-Aviv Sourasky Medical Center (N.M.B.), Tel Aviv, Israel; the Department of Public Health (J.T.), Hjelt Institute, University of Helsinki, Helsinki, Finland; and Hua Shan Hospital (Z.H.), Department of Neurology, Shanghai, PR China. The online-only Data Supplement is available with this article at /-/DC1. *Drs Hong and Heiss are co-corresponding authors. Correspondence to Wolf-Dieter Heiss, MD, Max-Planck Institut für Neurologie, Gleueler Strasse 50, Koeln, Germany. wdh@nf.mpg.de; or Zhen Hong, MD, Hua Shan Hospital, Department of Neurology, 12, Wulumuqi Zhong Road, Shanghai, , PR China. profzhong@sina.com 2012 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 Heiss et al Cerebrolysin in Patients With AIS in Asia 631 clinical trial to test the efficacy and safety of Cerebrolysin in patients with acute ischemic stroke was designed. 16 We report here the final results from this Cerebrolysin Acute Stroke Treatment in Asia trial (CASTA). Methods CASTA is a Phase IV clinical trial designed as a multicenter, randomized, double-blind placebo-controlled parallel-group study. 16 The study included patients with acute hemispheric ischemic strokes based on a clinical diagnosis from 51 centers from China (1024 patients), Hong Kong (4 patients), South Korea (16 patients), and Myanmar (26 patients). Patients with strokes of the brain stem or the cerebellum as well as patients with lacunar or hemorrhagic strokes were excluded. The severity of the neurological deficit at baseline was assessed using the National Institutes of Health Stroke Scale (NIHSS). Inclusion criteria were: male and female patients, age between 18 and 85 years with focal neurological deficit and a clinical diagnosis of acute hemispheric ischemic stroke with CT or MRI results compatible with a clinical diagnosis of acute hemispheric stroke, NIHSS score between 6 and 22 (both inclusive), and functionally independent before stroke with a prestroke Rankin Scale score of 0 or 1. Randomization and treatment with the trial medication initiated within 12 hours after stroke onset. Signed informed consent was obtained from the patient or the patient s legally accepted representative. The inclusion time of 12 hours was chosen based on results from experimental time window studies 10,11 and practicability assessed during the design of the study. Main exclusion criteria were evidence on CT/MRI of intracranial hemorrhage, decreased consciousness (defined as score of 2 on NIHSS Question 1a), neurological signs and symptoms that were likely to resolve completely within 24 hours, systolic blood pressure 220 mm Hg or diastolic blood pressure 120 mm Hg on repeated measurement, severe congestive heart failure or presentation with acute myocardial infarction, pre-existing systemic disease significantly limiting life expectancy, concomitant treatment with other neuroprotective or no-otropic drugs, and intolerance or contraindication to aspirin or Cerebrolysin. Intervention The study compared 2 groups of patients. They were either treated with 30 ml Cerebrolysin diluted in saline (total of 100 ml) at an intravenous infusion or with matched placebo (100 ml saline). Both groups received 100 mg aspirin orally as standard treatment. Treatment was administered as single daily dose for 10 days starting within 12 hours of stroke onset. A total of 90.2% of the patients in the Cerebrolysin group and 85.2% of the patients in the placebo group were still exposed to treatment at Day 10. The median number of doses administered per patient was 10 in both groups. Primary Efficacy Criteria The primary efficacy criterion was defined as the combined result of Barthel Index (BI), modified Rankin Scale (mrs), and the NIHSS evaluated in 1 global test. Primary end point for assessing efficacy was 90 days after the stroke event. Secondary Efficacy Criteria The secondary study end points included responder analysis based on responder definitions for mrs, BI, and NIHSS. Again, the criteria were evaluated combined into 1 global test. Before unblinding the study, a blind review of the data was performed. The review was within the framework of the requirements of the ICH Guideline E9. 17 The cutoff was reanalyzed during blind review and a cutoff at 9 points on the NIHSS was considered to be appropriate for all responder analyses due to the median baseline NIHSS. For the purpose of the treatment responder analysis, the definition of excellent outcome on the BI and mrs was stratified by baseline stroke severity. The final responder definitions were established during the blind review process (Table 1). Table 1. Responder Definitions for BI, mrs, and NIHSS Established During the Blind Review Scale Baseline NIHSS 9 Baseline NIHSS 9 BI Score of Score 60 mrs mrs of 0 1 mrs of 0 2 NIHSS Excellent outcome on the NIHSS was defined as an NIHSS score of 0 or 1 or an improvement from the baseline NIHSS score of 6 points BI indicates Barthel Index; mrs, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale. Additional secondary study end points included the global test as described for the confirmatory analysis, but this time evaluated for Day 30 instead of Day 90, quality-of-life assessment using the SF-12 at Day 90, overall death rate, and time to death. Stratified (Subgroup) Analyses There were 4 stratified analyses of the BI preplanned in the blind review with subgroups as follows: (1) stratification for thrombolysis therapy; (2) for age ( 65 years/age 65 years); (3) for severity of disease at baseline (NIHSS 7, NIHSS 8 12, NIHSS 12);and (4) side of infarction. Post Hoc Analyses Additionally, post hoc stratified analyses were performed, for example, for NIHSS and mrs (with strata as defined previously for BI). Furthermore, there were post hoc subgroup analyses for baseline NIHSS 17 points, study centers in Hong Kong and South Korea only, primary efficacy criterion in subgroup NIHSS 12, mortality in subgroup NIHSS 12, and responder in subgroup NIHSS 12. Safety Analyses Safety variables such as vital signs and laboratory data of all randomized subjects were summarized by descriptive statistics. Laboratory data were further evaluated by sign tests and shift tables. Adverse events were recorded throughout the study and categorized by body system, type of event, severity, and course. The frequencies of adverse events between groups were compared. Statistical Analysis Following the National Institute of Neurological Disorders and Stroke stroke trial, the confirmatory test was based on a directional global test of the efficacy variables NIHSS, BI, mrs (1-sided test for superiority, 97.5% CI). 18 We applied the Wei-Lachin procedure of the Wilcoxon-Mann-Whitney test. 19,20 It is the preferred analysis method if the outcome variables are not continuous or might have skewed distributions or outliers. The effect size measure associated with the Wilcoxon-Mann-Whitney test is the Mann Whitney statistic (MW). It defines the probability that a randomly selected patient of the treatment group is better off than a randomly chosen patient from the reference group. The following benchmark values hold for the test group under fairly general conditions: 0.50 equality, 0.56 small superiority, 0.64 medium-sized/relevant superiority, 0.71 large superiority. The primary analysis was based on the intention-to-treat population. Time to event data were described by Kaplan-Meier curves and evaluated using the Peto log-rank test. Other secondary efficacy criteria were evaluated with the Wilcoxon-Mann-Whitney test (1-sided test for superiority, 97.5% CI). Missing values were substituted by last observation carried forward. In patients who had died, a worst score correction was applied. Sample Size With an of (1-sided) and a 90% power, 495 patients per group are needed to detect a difference of MW This corresponds to a superiority of the verum group by 9.9 percentage points in 1 individual efficacy criterion, yet because of general uncertainties, the sample size was increased to 530 subjects.

3 632 Stroke March 2012 Figure 1. Disposition of patients in the study. Of 1070 patients randomized, 1 untreated patient was excluded from all evaluations. This leaves 1069 patients eligible for the safety evaluations. In 2 treated patients, there were no efficacy assessments so that the ITT population includes 1067 patients. One hundred fifty-nine patients of the ITT population showed major protocol violations resulting in 908 patients who could be included in the per-protocol population. ITT indicates intention-to-treat. Results From September 2005 to September 2009, 1070 patients were randomized. Of 1069 patients who received at least 1 infusion of study medication, 529 patients (49.5%) received Cerebrolysin and 540 patients (50.5%) placebo (Figure 1). There were no major differences in the baseline and efficacy characteristics among the treatment groups (Table 2). Sixtysix patients (12.5%) in the Cerebrolysin group and 93 patients (17.2%) in the placebo group showed major protocol violations. The most common cause was premature discontinuation not related to efficacy (Cerebrolysin 49 patients [9.3%]; placebo 66 patients [12.2%]). Sixty patients died and 890 (83.2% of all randomized patients) completed the 90-day follow-up. Two patients discontinued without any assessment of efficacy (1 due to an adverse event and the other due to violation of in-/exclusion criteria). A total of 373 patients out of 1067 patients of the intention-to-treat population (35.0%) entered the study with statin treatment. In the Cerebrolysin group, there were 183 patients treated with statins (34.7% of the patients in this group). In the placebo group, 190 patients (35.2%) had statin treatment at baseline. There was no noteworthy group difference. Only 1 patient (Cerebrolysin group) had a record of previous medication with Coumadin (treatment was continuing at study entry). Nineteen patients were treated with Coumadin during the course of the study (Cerebrolysin, 9 patients; placebo, 10 patients). Again, there are no substantial group differences. This was also the case for patients with atrial fibrillation. In the medical history section, 105 patients in the intention-totreat population (9.8%) had an entry explicitly describing atrial fibrillation (Cerebrolysin 48 patients [9.1%] and placebo 57 patients [10.6%]). Patients with more general records such as arrhythmia were not included. Primary Efficacy Criteria At Day 90, a median NIHSS improvement by 6 points was observed for Cerebrolysin (placebo: 5 points). For the BI, the median improvement was 30 points in both groups. Final median mrs score was 2 points in both groups. The global test resulted in MW 0.50, which expresses that there is no group difference found in the study patients. The lower bound

4 Heiss et al Cerebrolysin in Patients With AIS in Asia 633 Table 2. ITT Population: Comparison of Baseline Characteristics and Efficacy Variables Between the Treatment Groups Shows No Group Differences Characteristic Cerebrolysin (N 527) Placebo (N 540) Male sex, no., percent 314 (59.6%) 326 (60.4%) Mean age, y, SD 65.0 (12.22) 65.5 (11.71) Mean body mass index, 23.7 (3.04) 24.0 (3.20) kg/m 2,SD Mean time until Hospital 5.6 (3.00) 5.6 (3.75) Admission (hrs/sd) Mean time until start of 7.7 (5.97) 7.6 (3.69) treatment, h, SD* Thrombolysis treatment, 50 (9.49%) 44 (8.15%) no., percent Prevalence of risk factors, no., percent Hypertension 331 (62.8%) 332 (61.6%) Diabetes 108 (20.5%) 117 (21.7%) Arrhythmia 71 (13.5%) 90 (16.7%) Coronary heart disease 72 (13.7%) 86 (16.0%) Baseline efficacy criteria, median (range) NIHSS maximum (range, 9 (6 33) 9 (6 26) 0 42 points) Barthel Index maximum 30 (0 100) 30 (0 100) (range, points) Modified Rankin Scale maximum (range, 0 6 points) 4 (0 5) 4 (0 5) ITT indicates intention-to-treat; NIHSS, National Institutes of Health Stroke Scale. *Calculated from stroke onset. of the CI (CI-LB) is 0.47 (P 0.50) so that superiority of Cerebrolysin could not be demonstrated in the confirmatory analysis. Also, the findings for the individual criteria (mrs, BI, and NIHSS) did not show statistically significant group differences. The evaluation of the primary criterion based on the per protocol population depicted a result very similar to the confirmatory analyses. Secondary Efficacy Criteria (Preplanned) Responder Analyses The responder rate according to NIHSS was 47.9% for Cerebrolysin and 46.5% for placebo. Evaluation of the BI showed 44.0% responders in the Cerebrolysin group and 45.9% responders in the placebo group. According to the mrs definition, responder rates of 37.6% for Cerebrolysin and 38.5% for placebo were found. The global test showed results similar to the confirmatory analysis (MW 0.50; CI-LB, 0.47; P 0.57). Analyses of Mortality In the study, a total of 60 patients died. There were 28 deaths in the Cerebrolysin group and 32 deaths in the placebo group. After 90 days, the cumulative percentage of patients who died was 6.6% in the placebo group and 5.3% in the Cerebrolysin group. The hazard ratio is 1.26 (CI-LB, 0.75; P 0.19), which indicates a small superiority for the Cerebrolysin group. SF-12 Questionnaire The analysis of the SF-12 questionnaire did not result in a significant difference between treatment groups. The combined result was MW 0.50 (CI-LB, 0.46; P 0.60) when considering survivors only. An additional analysis with worst rank score correction for fatal outcome showed a very similar result. Preplanned Subgroup Analyses For the criterion BI, a preplanned stratification by severity of disease according to baseline NIHSS result was performed. In the strata NIHSS 7 (OR, 0.99; CI-LB, 0.79; P 0,45) and NIHSS 8 to 12 (OR, 0.97; CI-LB, 0.79; P 0.41), there were no group differences to be found. The same goes true for the subgroup with baseline NIHSS 12 (OR, 0.97; CI-LB, 0.73; P 0.41). The combined (ie, adjusted) result is OR 0.98 (CI-LB, 0.85; P 0.37) and does not indicate a superiority of Cerebrolysin. Also, other predefined subgroup analyses (side of infarction, stratification for age, and stratification for thrombolysis) did not indicate a statistical significant difference between the treatment groups. Post Hoc Analyses When the predefined stratification by severity was repeated with the criterion NIHSS, however, a small superiority for Cerebrolysin in the subgroup with baseline NIHSS 12 (OR, 1.27; CI-LB, 0.97; P 0.04) could be shown (Table 3). Also, when applying the mrs, a small superiority in the subgroup with baseline NIHSS 12 (OR, 1.27; CI-LB, 0.90; P 0.09) was found. The following analysis also focused on the subgroup baseline NIHSS 12 points only and provided a global test result for all 3 criteria combined. This global test results in MW 0.53 (CI-LB, 0.47; P 0.16), which showed a benefi- Table 3. NIHSS (Change From Baseline, LOCF), Descriptive Statistics for Subgroup Baseline NIHSS >12, ITT Population NIHSS Baseline Visit 2 Visit 3* Visit 4 Visit 5 Visit 6 Cerebrolysin Mean/SD Placebo Mean/SD NIHSS indicates National Institutes of Health Stroke Scale; LOCF, last observation carried forward; ITT, intention-to-treat. *Start of LOCF substitution.

5 634 Stroke March 2012 Figure 2. Kaplan-Meier survival curve (cumulative percentage) for subgroup baseline NIHSS 12 points (N 252, 126 patients per group); ITT population. HR, (CI-LB, 1.00; P in a 2-sided test with 0.05). NIHSS indicates National Institutes of Health Stroke Scale; ITT, intention-to-treat; HR, hazard ratio; LB, lower bound. cial trend for Cerebrolysin in the study patients. The findings for the individual criteria all showed a positive trend for superiority of the Cerebrolysin group. Very similar results could also be shown for patients with even more severe strokes (NIHSS baseline score 17). In this subgroup, the global test resulted in MW 0.54 (CI-LB, 0.42; P 0.28). Mortality in Subgroup NIHSS >12 Looking into mortality of the subgroup NIHSS 12, there were 252 patients with a baseline score in this range. In this subpopulation, 12 patients of the Cerebrolysin group died as compared with 22 patients in the placebo group. After 90 days, the cumulative percentage of patients who died is 20.2% in the placebo group but only 10.5% in the Cerebrolysin group. In the survival time analysis in the subgroup with baseline NIHSS 12 points, an even more pronounced superiority of Cerebrolysin can be seen (hazard ratio, ; CI-LB, ; P ). In a descriptive sense, this is a significant difference between the 2 treatment groups and a noteworthy advantage for the patients in the Cerebrolysin group (Figure 2). Safety Analyses A total of 1218 adverse events in 485 patients (242 in the Cerebrolysin and 243 in the placebo group) occurred in this study. Adverse events were assessed at each visit from screening/baseline (Day 1) to Visit 6 (Day 90). Eighty-nine serious adverse events occurred after start of the treatment (Cerebrolysin 50 serious adverse events, placebo 39 serious adverse events). Sixty of 1069 patients sustained fatal adverse events (Cerebrolysin 28 patients [5.3%] and placebo 32 patients [5.9%]). Of 1069 patients, 85 patients (8.0%) discontinued the study due to adverse events. 39 patients in the Cerebrolysin group (7.4%) and 46 patients in the placebo group (8.5%). The evaluation of adverse events did not show any noteworthy group differences. The same is true for the laboratory evaluation as well as the evaluation of vital signs and of concomitant medication so that there is no indication for a safety risk associated with Cerebrolysin treatment. Discussion This is the report of another large-scale clinical trial in acute ischemic stroke. A large clinical trial with Cerebrolysin was justified because this compound has complex properties including neuroprotective and neurotrophic activity demonstrated in preclinical 7 12 and small clinical studies Despite the previous promising results, this large doubleblind placebo-controlled randomized study (CASTA) did not show a significant difference between the Cerebrolysin and placebo groups in the primary end point. For the post hoc analysis, however, there was a beneficial trend in favor of Cerebrolysin. The outcome of CASTA might be affected by several peculiarities of the included patients population. One of them, and probably the most important factor, is the large number of mild strokes included in the trial. In the CASTA study, the median baseline NIHSS was 9 points in both groups, so that even within the allowed range, the typical patient included in the study had a low baseline NIHSS value indicating that he or she was suffering only from a mild stroke, in which a good prognosis in many cases can be expected. Based on results from earlier studies, it was expected that the median NIHSS would have been in the range of 12. Therefore, the unexpectedly high number of mildly affected patients in this study may have rendered the results inconclusive. In fact,

6 Heiss et al Cerebrolysin in Patients With AIS in Asia 635 only 60 of 1067 patients in the intention-to-treat population died during the course of the study resulting in 5.6% mortality in the observation period, which is, compared with previously published stroke trials like European Cooperative Acute Stroke Study (ECASS) I-II, 24,25 Stroke-Acute Ischemic NXY Treatment (SAINT)-1 23 and 2 26 or the dp-b99 trial 21 a very low rate. The only comparable mortality rate was seen in the ECASS III study. 22 Considering the low NIHSS at baseline and the low mortality rate, it was decided to carry out subgroup analysis in patients with NIHSS 12. Other important considerations are safety and adverse event profile. The incidence of serious and nonserious adverse events was similar in the 2 groups, as was the case in previous trials It may be assumed that even an effective treatment will hardly be able to further improve the generally good prognosis in patients with mild stroke as found in this study. Thus, the neutral result does not necessarily exclude the efficacy of Cerebrolysin in patients with stroke generally. Actually, there is some indication that Cerebrolysin might show a beneficial effect in patients with more severe strokes. The analysis of survival time including all patients showed a small advantage of Cerebrolysin treatment. This advantage was even larger in the subgroup with baseline NIHSS 12 points. In the subgroup NIHSS 12, there is a noteworthy advantage for the patients in the Cerebrolysin group. The validity of the study results is attested by several features. Patients and investigators remained strictly blinded to the treatment assignments, and the occurrence or nature of adverse events did not compromise the blinding either. Missing data were handled according to international standards or guidelines. 17 Prognostic factors that influence stroke outcome were well matched between treatment groups and showed, due to the general mild severity of strokes, a generally beneficial trend for the outcome. The per-protocol analysis confirmed the result of the intention-to-treat analysis. A large sample size in clinical trials offers the opportunity to explore subgroups still with an adequate sample size. The results of post hoc subgroups evaluated in this trial provide a chance to improve patient selection for future trials. 27 Based on this information and the mode of action of Cerebrolysin with pleiotropic and multimodal effects that allows interference on several pathopysiological processes, 5,6,9 12,14 the potential positive effects of Cerebrolysin should be further evaluated in an appropriately designed follow-up study. This trial should focus on patients with more severe stroke and could be designed to prolong the treatment with Cerebrolysin by booster treatments to take advantage of both the neuroprotective and neuroregenerative action, which might support neurorehabilitative measures and thereby improve the longterm outcome after ischemic stroke. In conclusion, the results from the present study show that Cerebrolysin can be applied safely and according to the post hoc subgroup analyses may provide beneficial effects in acute ischemic stroke. Another confirmatory study is needed to determine whether Cerebrolysin has a clearly significant benefit in patients with moderate to severe stroke. Acknowledgments Statistical design, data analysis, and statistical support throughout the study and for preparing the article were performed and provided by Idv Gauting, Germany. We acknowledge the 51 participating study centers ( Sources of Funding This study was funded by EVER Neuro Pharma GmbH, Oberburgau 3, Austria. The steering committee, safety committee, and other study investigators were working independently. The sponsor assisted in the writing of the protocol, selection of study sites, data collection, and project management. The statistical data analysis was carried out by an independent statistical consultant from Idv Gauting, Germany. The interpretation of results and conclusions are those of the authors, and these and writing of the article were not influenced by the sponsor. The article was reviewed and approved by the independent steering committee and safety committee. The authors received an honorarium related to this work from the sponsor and support for travel. Disclosures Dr Heiss is an advisor for EVER Neuro Pharma and received honoraria for this activity. He is active in the speaker s bureau of EVER Neuro Pharma and CoAxia and he receives support from the Wolf-Dieter Heiss Foundation. Dr Brainin has received financial support for research grants from EVER Neuro Pharma and Boehringer Ingelheim and other research support from the European Research Foundation and Life Science Krems. He is in the speaker s bureau of Allergan, Boehringer Ingelheim, Ferrer, Pfizer, and EVER Neuro Pharma. He is active as a consultant and advisor for Allergan and EVER Neuro Pharma. Dr Bornstein is a consultant for EVER Neuro Pharma and received honoraria for this activity. He is also active in the speaker s bureau of EVER Neuro Pharma. 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