The efficacy and safety of Fufangdanshen tablets (Radix Salviae miltiorrhizae formula tablets) for mild to moderate vascular dementia: a study protocol for a randomized controlled trial

Vascular dementia (VaD) is the second most common subtype of dementia after Alzheimer’s disease (AD) [1], and it accounts for 11.1–15.8 % of all cases of dementia worldwide [2, 3]. The EURODEM Prevalence Research Group compared the prevalence of VaD in five datasets from Europe (Finland, Italy, Sweden, and two from the United Kingdom) and found that the prevalence ranged from 0.0–1.6 % for those aged between 60 and 70 years and increased to 2.8–9.2 % for subjects aged 80–90 years. The annual incidence rate was estimated to be 3.79 per 1000 among non-demented populations. At present, the treatment of VaD focuses on primary and secondary prevention strategies because randomized clinical trials in VaD have not been able to demonstrate clinically relevant symptomatic improvement. Additionally, it has not yet been possible to establish disease-modifying effects in VaD syndrome [4]. Thus, the development of an effective treatment for VaD is important.

Fufangdanshen tablets (FFDS), a traditional herbal medicine approved by the China Food and Drug Administration (CFDA) in 2008 (Number: [2008]1919), are extracted from the Chinese herbs Salvia miltiorrhiza, Panax notoginseng, and Borneolum syntheticum and contain tanshinone, salvianolic acid, panax notoginsenosides, ginsenoside Rb1, ginsenoside Rg1, and borneol. The tablets are used to treat patients with VaD. Preclinical studies have shown that tanshinone can improve the impaired learning and memory induced by A?1-40 in rat models of AD [5], inhibiting AD-induced expression levels of inducible nitric oxide synthase (iNOS) and matrix metalloproteinase II (MMP-2), reducing toxic free radicals, and suppressing oxidative injury in AD rats [6]. Salvianolic acid can inhibit glutamate release and anti-cerebral ischemic effects [7]. Borneol can improve the permeability of the blood-brain barrier [8].

Many studies have reported that FFDS tablets can improve the memory of demented mice [9] and improve the impairment of spatial discrimination and memory impairment in rat models of AD. The mechanisms may involve improvement in the brain choline acetyl transferase (ChAT) activity that is decreased in AD rats and induced by A? [10], lowering the toxicity of excitatory amino acids [11] and increasing the expression of vascular endothelial growth factor (VEGF) in the brains of rats during chronic cerebral ischemia [11]. Additionally, FFDS tablets could improve the learning and memory capabilities in rat models of VaD, increase the activity of superoxide dismutase, and reduce neuron apoptosis in the hippocampus [12].

A phase II clinical trial on the efficacy of FFDS tablets in VaD was carried out in five centers. The trial enrolled 231 patients; all patients were randomized to the FFDS tablets group (115 patients) or the dihydroergotoxine mesylate tablets group (116 patients). Scores on the Mini Mental State Examination (MMSE) [13] and activities of daily living significantly improved in both groups compared with baseline (P??0.001). However, there were some limitations to this study. First, there was no placebo group. As all subjects knew that they were being treated with one of two drugs and all of the individuals who assessed the patients knew this as well, the results may have been influenced by a positive response bias. Second, the sample size was relatively small. Third, this previous study only followed up patients for 12 weeks, and this period of follow-up was too short to detect the effects of the drugs.

To further investigate the safety, tolerability, and efficacy of FFDS tablets in the treatment of mild to moderate VaD, we designed and report the methodology for a 24-week randomized, double-blind, parallel, multicenter clinical study.