Cerebrolysin and Recovery After Stroke (CARS): A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial

Abstract

Background and purpose: The aim of this trial was to investigate whether stroke patients who receive Cerebrolysin show improved motor function in the upper extremities at day 90 compared with patients who receive a placebo.

Methods: This study was a prospective, randomized, double-blind, placebo-controlled, multicenter, parallel-group study. Patients were treated with Cerebrolysin (30 mL/d) or a placebo (saline) once daily for 21 days, beginning at 24 to 72 hours after stroke onset. The patients also participated in a standardized rehabilitation program for 21 days that was initiated within 72 hours after stroke onset. The primary end point was the Action Research Arm Test score on day 90.

Results: The nonparametric effect size on the Action Research Arm Test score on day 90 indicated a large superiority of Cerebrolysin compared with the placebo (Mann-Whitney estimator, 0.71; 95% confidence interval, 0.63-0.79; P<0.0001). The multivariate effect size on global status, as assessed using 12 different outcome scales, indicated a small-to-medium superiority of Cerebrolysin (Mann-Whitney estimator, 0.62; 95% confidence interval, 0.58-0.65; P<0.0001). The rate of premature discontinuation was <5% (3.8%). Cerebrolysin was safe and well tolerated.

Conclusions: Cerebrolysin had a beneficial effect on function and global outcome in early rehabilitation patients after stroke. Its safety was comparable with that of the placebo, suggesting a favorable benefit/risk ratio. Because this study was exploratory and had a relatively small sample size, the results should be confirmed in a large-scale, randomized clinical trial.

Clinical trial registration: URL: http://www.clinicaltrialsregister.eu. Unique identifier: 2007-000870-21.

Keywords: Cerebrolysin; randomized, double-blind, placebo-controlled trial; recovery of function; rehabilitation; stroke.

Figure 1.

A, Time course of the Action Research Arm Test (ARAT) with Cerebrolysin (30 mL/d) and the placebo, shown as boxplot diagrams (P10 and P90) for days 7 (V3), 14 (V4), and 21 (V5) post baseline and days 42 (V6) and 90 (V7) post stroke. The modified intention-to-treat (mITT) population was analyzed using the last observation carried forward (LOCF) approach for handling missing data. The mITT-LOCF population on day 90 included a total of 205 patients (Cerebrolysin, n=104; placebo, n=101). B, Effect sizes (Mann–Whitney) of the ARAT score changes from baseline in the mITT-LOCF population. Analyses were conducted using the Wilcoxon–Mann–Whitney test.

Figure 2.

Distribution of modified Rankin Scale scores. Cumulative percentage (Cerebrolysin vs placebo): 8.65 vs 2.97 (0), 42.31 vs 14.85 (1), 65.38 vs 33.66 (2), 88.46 vs 75.25 (3), 98.08 vs 96.04 (4), and 100.0 vs 100.0 (5). Definitions of scores: 0=no symptoms at all; 1=no significant disability despite symptoms: able to carry out all usual duties and activities; 2=slight disability: unable to carry out all previous activities but able to look after own affairs without assistance; 3=moderate disability: requiring some help, but able to walk without assistance; 4=moderately severe disability: unable to walk without assistance and unable to attend to own bodily needs without assistance; 5=severe disability: bedridden, incontinent, and requiring constant nursing care and attention; and 6=dead.

Figure 3.

Global status on day 90. The effect sizes (Mann–Whitney [MW]) for the single and combined (Wei–Lachin procedure) efficacy parameters reflect changes from baseline in the modified intention-to-treat–last observation carried forward population (n=205). Analyses were conducted using the multivariate, directional Wilcoxon test. MCS indicates mental component summary; mRS, Modified Rankin Scale; and PCS, physical component summary.