Ladurner 2005.

Study characteristics
Methods	Study design: multicentre, randomised, double‐blind controlled trial Mean duration of follow‐up: 90 days Study grouping: parallel group Loss to follow‐up: 15 of 146 (10%) Trial protocol registration: no protocol identified
Participants	Baseline characteristics: Cerebrolysin Age: 65 years ± 1.17 Men: 47 (60.3%) Women: 31 (39.7%) Total number: 78 Handedness: left: 1 (1.3%); right: 77 (98.7%) Stroke location: left hemisphere: 41 (52.6%); right hemisphere: 37 (47.4%) Duration of symptoms (values are means ± SEM): 12.3 hours ± 0.73 CNS (values are means ± SEM): 6.88 ± 0.09 GCS (values are means ± SEM): 14.1 ± 0.20 Placebo Age: 65 years ± 1.32 Male: 38 (55.9%) Female: 30 (44.1%) Total number: 68 Handedness: left: 0 (0%); right: 68 (100%) Stroke location: left hemisphere: 31 (45.6%); right hemisphere: 37 (54.4%) Duration of symptoms (values are means ± SEM): 13.5 hours ± 1.16 CNS (values are means ± SEM): 6.68 ± 0.14 GCS (values are means ± SEM): 14.4 ± 0.16 Inclusion criteria: men and women suffering from their first acute ischaemic stroke with clinical symptoms of middle cerebral artery area were enrolled. Patients were eligible if they were admitted to the hospital and received the first dose of study medication within 24 hours of the onset of the stroke and were between 45 and 85 years of age at study entry. Participants were also required to have a GCS score of greater than 10 and a CNS score between 4.5 and 8.0 at baseline. Exclusion criteria: people with haemorrhagic strokes, transient ischaemic attacks, uncontrollable hypertension, acute myocardial infarction, congestive heart failure, moderate‐severe dementia prior to the stroke, coma or stupor, other severe concomitant diseases, impaired renal function, and people with a history of prior stroke Pretreatment: 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 2 groups
Interventions	Cerebrolysin Frequency of dosage: Cerebrolysin 50 mL was administered once daily for 21 days by intravenous infusion in a peripheral vein over a period of 20 minutes. Cerebrolysin mixed with 50 mL of normal saline Standard treatment: pentoxifylline (300 mg/day, intravenous) and acetylsalicylic acid (250 mg/day, orally) for the first 21 days, and pentoxifylline (2400 mg/day, orally) and acetylsalicylic acid (250 mg/day, orally) from day 22 to the end of the study at day 90 Placebo Frequency of dosage: placebo was administered once daily for 21 days by intravenous infusion in a peripheral vein over a period of 20 minutes. Placebo contained 100 mL of normal saline. Standard treatment: pentoxifylline (300 mg per day, intravenous) and acetylsalicylic acid (250 mg/day, orally) for the first 21 days, and pentoxifylline (2400 mg/day, orally) and acetylsalicylic acid (250 mg/day, orally) from day 22 to the end of the study at day 90
Outcomes	Poor functional outcome defined as death or dependence at the end of the follow‐up period (dichotomous outcome) Early death (dichotomous outcome) All‐cause death (dichotomous outcome) Serious adverse events (dichotomous outcome) Adverse effects specifically associated with Cerebrolysin (dichotomous outcome) Total number of participants with adverse events (dichotomous outcome)
Identification	Sponsorship source: EBEWE Pharma Country: Austria, the Czech Republic, Hungary Setting: inpatient (hospital) Authors: Dr G Ladurner and H Moessler Institution: Department of Neurology, Christian‐Doppler Hospital, Salzburg, Austria Email: g.ladurner@lks.at and herbert.moessler@ebewe.com
Notes	Population: concomitant use of nootropic drugs (e.g. piracetam), drugs with dilatating effects on peripheral blood vessels (naftidrofuryl, cinnarizine, flunarizine, nimodipine), as well as chronic intake of antidepressants, tranquillisers, sedatives, or CNS stimulants was prohibited throughout the study No study protocol identified.
Risk of bias
Bias	Authors' judgement	Support for judgement
Allocation concealment	Unclear risk	Quote: "For each patient a sealed envelope with information on the actual treatment dispensed was provided to the investigator for emergency cases. All envelopes remained sealed throughout the study." Comment: sealed envelopes were used to conceal allocation, but it was not mentioned if they were opaque. Adding to the unavailability of study protocol, we judged this as unclear risk of bias.
Sequence Generation	Low risk	Quote: "Patients who met all entry criteria were assigned to the treatment groups in a 1:1 ratio, according 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." Comment: the computer software used to generate the random numbers was provided by EBEWE Pharma, which is also the provider of Cerebrolysin
Incomplete outcome data All outcomes	High risk	Quote: "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)." Comment: attrition bias, 25 out of 146 randomised participants were lost to follow‐up (17%). Information on the outcomes of interest to this review was available only for serious adverse events including death. Furthermore, the study authors used the 'last observation carried forward' (LOCF) method to fill in the missing data points. There is not a single peer‐reviewed statistical publication that describes general conditions under which LOCF provides a statistically unbiased result.
Blinding of outcome assessors All outcomes	Low risk	Quote: "The investigators and all other study personnel were blind as to the random code assignment until the completion of the statistical analysis."
Selective outcome reporting	Unclear risk	Quote: "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." Quote: "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 relationship to the study drug for any other of the SAEs, as per the investigator’s assessment." Comment: the trial authors did not report on the time when deaths occurred, and did not assess potential causality with administered medicines. Furthermore, the authors used the 'last observation carried forward' (LOCF) method to fill in the missing data points. There is not a single peer‐reviewed statistical publication that describes general conditions under which LOCF provides a statistically unbiased result.
Blinding of participants and personnel All outcomes	Low risk	Quote: "The investigators and all other study personnel were blind as to the random code assignment until the completion of the statistical analysis." Comment: impossible to assess blinding by outcome
Other sources of bias	Unclear risk	Quote: "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 University, FNKV, Department of Neurology, Prague; F. Stockenhuber, Landeskrankenhaus, Oberpullendorf, Austria; Z. Haffner, Petz Alada ´Megyei Koorha'z, Gyoor, Hungaria; P. Ridzon, Thomayer’s Hospital, Praha, Czech Republic; E. Diabl, Linz General Hospital, Linz, Austria." Quote: "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." Comment: there was no information on funding sources for the trial, and no conflict of interest statement was provided. EBEWE Pharma provided the medication and randomisation codes. No study protocol publicly available