New Approaches to Clinical Trials in Vascular Dementia: Memantine in Small Vessel Disease

Abstract

Although criteria for the diagnosis of vascular dementia (VaD) are established, the diagnostic concept is still controversial and there is no regulatory guidance for clinical drug development. Clinical trials in VaD present a number of pitfalls and challenges and, so far, no compound has received regulatory approval for this indication. The methodological issues of clinical VaD trials are discussed using the development of memantine for this indication as an example. In a pooled analysis of two placebo-controlled trials with the NMDA-antagonist memantine in VaD, the cognitive benefit by memantine treatment was more pronounced for patients with ‘small vessel disease’ than for those with other neuroradiological findings at baseline. In a subgroup of patients with ‘large vessel disease’ or macrolesions, there was less cognitive decline among the placebo patients. It may therefore be helpful to use predefined diagnostic subcategories in clinical studies in this indication. The findings further suggest that stroke or multiple infarctions may not be the primary reason for cognitive decline in VaD patients.

The Science of Stroke: Mechanisms in Search of Treatments

“…As a result, the dosing may have been suboptimal, due to the development of untoward side effects that prevented dose escalation to neuroprotective levels. A more suitable approach would be to use therapeutic agents that selectively target excessive channel opening (e.g., uncompetitive inhibitors with a relatively fast off-rate, such as memantine (Orgogozo et al, 2002; Mobius and Stoffler, 2002; Lipton, 2006; Kaviragan and Schneider 2007) thereby retaining normal receptor functions (Lipton, 2007a). …”

Emerging Therapies for Vascular Dementia and Vascular Cognitive Impairment

“…In addition, placebo decline of the small-vessel group was clearly more pronounced than in the large-vessel type of VaD. 66 …”

“…Patients with MMSE score Ͻ15 at baseline showed an ADAS-cog improvement of 3.2 points over placebo. 66 Additionally, the cognitive treatment effect for memantine was more pronounced in the small-vessel type group without cortical infarctions by CT or MRI. In addition, placebo decline of the small-vessel group was clearly more pronounced than in the large-vessel type of VaD.…”

Cerebral small vessel disease: how does it progress?

“…Effects of Memantine in VD were studied in two large double-blind six-month studies. A post hoc subgroup analysis found that placebo-treated SVD patients worsened by a mean of 1.9 ADAS-cog points, while largevessel VD patients remained nearly unchanged [32]. In a small open 22-month study dedicated specifically to SVD, Moretti et al [33] compared the effects of Rivastigmine vs. cardioaspirin in eight patients each.…”