Synergistic treatment effects with Cerebrolysin and donepezil: Results from a randomized, double-blind, multicenter trial to compare safety and efficacy of Cerebrolysin, donepezil and a combination treatment in patients with probable Alzheimer's disease

Background: Cerebrolysin is a peptide preparation acting in a similar way like neurotrophic factors. This study investigated possible synergistic treatment effects by combining a treatment targeting the neurotrophic axis (Cerebrolysin) with a treatment improving cholinergic neurotransmission (donepezil). Methods: Patients suffering from mild to moderate AD (MMSE 12-25) were enrolled in this trial and randomized in a ratio of 1:1:1 to 10ml Cerebrolysin, 10mg donepezil or both. Primary endpoints were change from baseline in ADAS-cog+ and CIBIC+ score at week 28. Secondary endpoints included the ADCS-ADL and the NPI. Efficacy analyses were based on the ITT data set using LOCF and PP. Results: Of 217 patients randomized, 197 patients were included in the ITT data set (females 77. 2%; age 75.2 years). A significant superiority of Cerebrolysin to donepezil and a marginal significant superiority of the combination to donepezil in the overall clinical functioning (CIBIC+) was shown at week 28. In the other domains tested, there was no statistically significant difference between treatment groups. However, best and similar results were obtained with Cerebrolysin and the combination for the cognitive domain (ADAS-cog+), the global clinical impression (CIBIC+) and the activities of daily living (ADCS-ADL). In the neuropsychiatric symptoms (NPI), monotherapy was superior to the combination and Cerebrolysin to donepezil. Similar results were observed in the PP analysis set. Cerebrolysin in a dose of 10ml given as monotherapy or in combination with donepezil was safe and well tolerated. The incidence of treatment-emergent AEs was similar in all treatment groups, however, gastrointestinal disorders were reported more frequently with donepezil (monotherapy or in combination), nervous system disorders with Cerebrolysin (monotherapy or in combination) and psychiatric disorders with the combination therapy. Four patients suffered from an SAE. Analyses of lab parameters, vital signs, physical and neurological examinations did not show any group-specific differences or relevant changes. Conclusions: These results have shown that therapy with Cerebrolysin is as good as with donepezil and descriptively even better and that a combination of neurotrophic treatment (Cerebrolysin) with cholinesterase inhibitors (donepezil) is a safe treatment option and provides synergistic treatment effects in patients suffering from mild to moderate Alzheimer's disease.