Cerebrolysin Trial in Stroke Fails to Meet Primary Endpoint But Shows Positive Signal for Severe Cases

Daniel M. Keller, PhD

October 20, 2010

October 20, 2010 (Seoul, South Korea) — Results of a large multicenter randomized trial have shown there to be no overall effect of administering Cerebrolysin (EVER Neuro Pharma GmbH) for patients with acute ischemic stroke, in contrast to previous clinical trials that had shown benefit.

Results of the Cerebrolysin in patients with Acute ischemic STroke in Asia (CASTA) trial were presented here at the 7th World Stroke Congress.

Lead author Wolf-Dieter Heiss, MD, from the Max Planck Institute for Neurological Research in Cologne, Germany, said one explanation may be that the patients in CASTA had, on average, mild strokes and that such patients might recover after receiving only standard care — a so-called ceiling effect, with no further benefit from Cerebrolysin.

Fortunately, the drug appeared very safe, which is a good omen for possible future trials investigating its effects in more severely affected stroke patients.

The study was funded by EVER Neuro Pharma GmbH.

Neuroprotective Effects

Consisting of low-molecular-weight peptides and free amino acids in solution, Cerebrolysin has pleiotropic mechanisms of action and multimodal effects, including neuroprotective, neurotrophic, and neuroregenerative ones. It also interferes with different elements in pathological cascades, Dr. Heiss explained. Cerebrolysin is approved outside the United States for the treatment of Alzheimer's disease and has also been used to treat traumatic brain injury.

Preclinical studies in the setting of stroke have shown that this agent reduces infarct volume and promotes functional recovery. Clinical trials involving a total of more than 1500 patients have proceeded since 1994, showing good results on motor function, activities of daily living, cognitive performance, and faster recovery for patients treated with recombinant tissue plasminogen activator and, additionally, with Cerebrolysin.

CASTA was a large, double-blind controlled multicenter clinical trial of Cerebrolysin designed to assess the clinical efficacy and safety of a 10-day course of daily intravenous administration of the drug (30 mL) plus 100 mg aspirin orally compared with placebo injection plus aspirin, begun within 12 hours of the onset of symptoms.

The trial was conducted in 52 centers across Asia and involved 1069 patients in the safety population (529 patients in the treatment group and 540 in the placebo group) and 1067 patients in the intention-to-treat population (527 and 540 patients, respectively).

The 2 treatment groups were well matched for stroke severity and other baseline data. The median scores were the same on all stroke scales: National Institutes of Health Stroke Scale (NIHSS; scale of 0 - 42 points) score of 9, Barthel Index (scale of 0 - 100 points) score of 30, and modified Rankin Scale (mRS; scale of 0 - 6 points) score of 4.

Hospital admission occurred at about 5.6 hours in each group, and treatment started at 7.7 ± 5.97 and 7.6 ± 3.68 hours in the treatment and placebo groups, respectively, after onset of symptoms. The groups were also well matched for stroke location and neurological signs and symptoms.

A statistical analysis (Wei-Lachin procedure) expressing the 3 primary efficacy criteria — mRS, Barthel Index, and NIHSS — on day 90 as a single global directional test constituted the primary endpoint.

"The test result, it's a little bit disappointing," Dr. Heiss told the audience. "The global test result is a mean value of .5, which expresses that there is no group difference found in the study patients." All responder analysis stratified by baseline stroke severity showed a neutral result and no treatment effect of Cerebrolysin.

The median NIHSS was just 9 in CASTA, which was low compared with most previous trials. Dr. Heiss said the mortality rate was also low, at 5.4%, indicating mild strokes, as opposed to rates ranging from about 8% to 32% in other Cerebrolysin studies.

The safety and tolerability of Cerebrolysin was very good in CASTA, similar to other trials, with no significant difference in the rate of adverse effects (AEs) and serious AEs (SAEs) between the 2 groups. The Cerebrolysin safety population experienced 585 AEs and 46 SAEs. For the placebo group, AEs occurred in 611 and SAEs in 38 patients. Discontinuations for AEs were 5.3% in the treated group and 6.5% for those receiving the placebo. In the Cerebrolysin group, 5.1% suffered fatal AEs compared with 5.7% in the placebo group.

Mortality was reduced by 1.3 percentage points in the Cerebrolysin group compared with the placebo group at 90 days (5.3% vs 6.6%). Most of the deaths in each group occurred by day 40.

A subgroup analysis by severity of the stroke as expressed by NIHSS score indicated a trend for beneficial effects of Cerebrolysin in the more severely affected subgroup (NIHSS, >12 vs ≤7 at baseline).

In the most severely affected subgroup, Cerebrolysin was associated with a 27% benefit in outcome (odds ratio, 1.27; 95% confidence interval, 0.97 - 1.67) compared with the placebo group. Dr. Heiss took this result as a "clear sign" that the mild cases caused a ceiling effect.

Cerebrolysin also showed a trend toward benefit in NIHSS and mRS for the more severely affected patients. Overall, there was a low mortality rate, and treated patients did at least as well as the placebo patients in this regard. The drug was safe and well tolerated.

Dr. Heiss said that based on the results of previous trials and the positive trends from the subgroup analyses in the CASTA trial, the trial steering committee feels that a further trial with an adjusted protocol is in order.

Recommendations are to use a higher dose of Cerebrolysin, to use a combination of acute and long-term treatment to promote recovery, and to exclude mildly affected patients.

Further Trials Warranted

Session moderator Bo Norrving, MD, professor of neurology at Lund University in Sweden and World Stroke Organization president and congress cochairman, told Medscape Medical News that a further trial of Cerebrolysin is "absolutely necessary," as CASTA was the first trial that was not positive for this drug, which is available and being used.

The positive trend in the trial "is a very important positive signal," he said. Future trials will most likely be tailored to look at patients with more severe strokes.

Cerebrolysin "has a very favorable safety profile" and is easy to use without SAEs, which, Dr. Norrving points out, has been a drawback for many other drugs in the past.

The study was supported by EVER Neuro Pharma GmbH of Austria. Dr. Heiss revealed financial relationships with EVER NeuroPharma and CoAxia. Dr. Norrving reported that he has received honoraria from Allergan, Bayer, and Boehringer and has done clinical trials work on endpoints committees with Servier, PhotoThera, and Syngis Pharma AG.

7th World Stroke Congress: Plenary III: Large Clinical Trials Closing Session. Presented October 16, 2010.

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