Studies were selected for inclusion method if they fulfilled the criteria of: phase III RCTs of patients with a diagnosis of AD and treated with memantine 20 mg/day added to stable ChEI; a double-blind observation period of at least 24 weeks, and a majority of patients receiving stable treatment with donepezil. Two studies met the inclusion criteria (MEM-MD-02 and MEM-MD-12), both of which were performed in multiple centres in the US [16,17]. Study approval was granted by the local Institutional Review Board (IRB) at each trial site, and written informed consent was obtained from each study participant if possible, and either the caregiver or a legally acceptable representative (if different from the caregiver) before initiation of study-specific procedures according to IRB protocols [16,17].

Figure 1 Patient flow. a5 to 10 mg/day for ?? 3 months. b5 or 10 mg/day donepezil; 6, 9 or 12 mg/day rivastigmine; 16 or 24 mg/day galantamine for ?? 3 months. MMSE, Mini-Mental State Examination; ChEI, cholinesterase inhibitor; ITT, intention-to-treat; … Full details of individual study design and patient inclusion criteria for MEM-MD-02 and MEM-MD-12 have been presented previously [16,17]. In summary, the patient inclusion criteria were similar: 50 years of age or older; diagnosis of probable AD according to the NINCDS-ADRDA criteria; a brain magnetic resonance imaging or computed tomographic scan within 12 months consistent with a diagnosis of probable AD; and treatment with a ChEI for at least 6 months with a stable dosing regimen for at least 3 months.

The individual clinical study inclusion criteria differed in the required baseline MMSE score (see Figure ?Figure1)1) and the allowed ChEI (only donepezil use in MEM-MD-02; any ChEI in MEM-MD-12). In both studies, patients treated with memantine received a fixed total dose of 20 mg/day. Selection was restricted to patients receiving stable treatment with donepezil 10 mg/day. Two subgroups of patients were analysed: the MOD to SEV subgroup of patients Batimastat with moderate to severe AD (MMSE < 20, range 5 to 19), conforming to the approved indication of memantine in the EU, and the MOD subgroup of patients with moderate AD (MMSE 10 to 19), conforming to the overlap of the approved memantine and donepezil indications in the EU.

Trial registration The data were obtained from the sponsors of the original trials; trial registration certainly was not relevant to these two studies since both studies were completed before July 1, 2005; MEM-MD-02 was completed by June 2002, and MEM-MD-12 was completed by March 2003 [16,17]. Efficacy measures Cognition was assessed using the Severe Impairment Battery (SIB) [18-20] in study MEM-MD-02 (patients with moderate to severe AD) and the ADAS-Cog [21] in study MEM-MD-12 (patients with mild to moderate AD). In both studies, function was assessed using the AD Cooperative Study – Activities of Daily Living scale (ADCS-ADL) [22,23].