Abstract: We identified six RCTs (1501 participants) that met the inclusion criteria. We evaluated risk of bias and judged it to be unclear for generation of allocation sequence in four studies and low in two studies; unclear for allocation concealment in five studies and low in one study; high for incomplete outcome data (attrition bias) in five studies and unclear in one study; unclear for blinding; high for selective reporting in four studies and unclear in two; and high for other sources of bias in three studies and unclear in the rest. The manufacturer of cerebrolysin, pharmaceutical company EVER Neuro Pharma, supported three multi-centre studies, either totally, or providing cerebrolysin and placebo, randomisation codes, research grants, or statisticians. None of the included trials reported on poor functional outcome defined as death or dependence at the end of the follow-up period or early death (within two weeks of stroke onset). All-cause death: we extracted data from five trials (1417 participants). There was no difference in the number of deaths: 46/714 in cerebrolysin group versus 47/703 in placebo group; risk ratio (RR) 0.91 95% confidence interval (CI) 0.61 to 1.35 (5 trials, 1417 participants, moderate-quality evidence). Serious adverse events (SAEs): there was no significant difference in the total number of SAEs with cerebrolysin (RR 1.16, 95% CI 0.81 to 1.67). This comprised no difference in fatal SAEs (RR 0.90, 95% CI 0.59 to 1.38) and an increase in the number of people with non-fatal SAEs (20/667 with cerebrolysin and 8/668 with placebo: RR 2.47, 95% CI 1.09 to 5.58, P = 0.03) (3 trials, 1335 participants, moderate-quality evidence). Total number of people with adverse events: three trials reported on this. There was no difference in the total number of people with adverse events: 308/667 in cerebrolysin group versus 307/668 in placebo group; RR 0.97 95% CI 0.86 to 1.09, random-effects model (3 trials, 1335 participants, moderate-quality evidence). The findings of this Cochrane Review do not demonstrate clinical benefits of cerebrolysin for treating acute ischaemic stroke. We found moderate-quality evidence of an increase in non-fatal SAEs with cerebrolysin use but not in total SAEs.

Plain-language summary: This review included six RCTs with a total of 1501 participants that compared cerebrolysin with placebo (inactive medication) added to standard treatment of acute stroke, including thrombolysis. Three of them were large multicentre studies, two were small in size and were judged to be of unclear quality, and one did not include numerical results. The evidence is current up to June 2016. This review of six trials involving 1501 participants showed no beneficial effect of cerebrolysin in terms of death in people with acute ischaemic stroke. There was no difference in the total number of people with adverse events but a concern that cerebrolysin may increase the risk of people having non-fatal serious adverse events compared with placebo. The medication and methodology of the majority of included trials were provided by the manufacturer of cerebrolysin creating a likely conflict of interest. There is moderate-quality evidence currently available that suggests cerebrolysin performs no better than placebo in terms of all-cause death when given to people with acute ischaemic stroke within 48 hours of stroke onset. There is moderate-quality evidence that raises concerns about the increase of serious adverse events with cerebrolysin use in people with acute ischaemic stroke. Further research is likely to have an important impact on our confidence in the estimate of cerebrolysin risks in contributing to serious adverse events in people with acute stroke.