Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which patients typically lose cognitive faculties, struggle to carry out activities of daily living (ADLs), and experience behavioural and neuropsychiatric problems. At present, AD cannot be cured, any improvements produced by pharmacotherapy are often temporary, and no treatments have been demonstrated to be disease-modifying. Consequently, alleviating symptoms, and delaying or reducing clinical worsening (that is, symptom progression), without modifying the underlying pathophysiology, are realistic and meaningful treatment goals  that can be termed disease-course-modifying effects . Achieving these goals allows patients to spend more time in the milder, more functional, stages of AD than they would without treatment .
Memantine, an uncompetitive antagonist of N-methyl-D-aspartate (NMDA) glutamate receptors, is approved in the EU and US for the treatment of patients with moderate to severe AD (Mini-Mental State Examination [MMSE]  score < 20). Donepezil, a cholinesterase inhibitor (ChEI), is approved for the treatment of mild to moderate AD in the EU, and for mild, moderate, and severe AD in the US and some other countries. As monotherapy, both memantine and donepezil have demonstrated efficacy for treating the symptoms of AD within their respective approved indications [4–12]. In addition, the incidence of clinical worsening, as defined by concurrent deterioration in three domains (cognitive, functional, and global) over time, is reduced by memantine treatment in patients with moderate to severe AD , and by donepezil treatment in patients with mild to moderate AD .
Since memantine and donepezil have different and complementary mechanisms of action, together they potentially offer additional benefits to the patient . Pharmacokinetic and pharmacodynamic data in healthy volunteers provided initial evidence that memantine and donepezil may be safely used in combination . The addition of memantine to stable ChEI therapy has also been associated with a good safety profile in patients with AD [16, 17].
Two 24-week, randomised, double-blind, placebo-controlled trials (RCTs) have investigated the efficacy and safety of memantine 20 mg/day in combination with a ChEI. The first, MEM-MD-02, assessed the efficacy of administration of memantine (10 mg twice daily) versus placebo in patients with moderate to severe AD (MMSE 5-14; n = 404) receiving stable donepezil therapy . Relative to placebo, memantine produced significant benefits in all four key symptom domains of AD, namely, cognition, function, behaviour, and global status . The second RCT, MEM-MD-12, assessed the efficacy of administration of memantine (20 mg once daily) versus placebo in patients with mild to moderate AD (MMSE 10-22; n = 433) taking a stable dose of any approved ChEI therapy . In this trial, the only potential signal of benefit for memantine treatment over placebo (effect size estimate 0.118 in favour of memantine; P = 0.184) was observed for the cognitive measure (AD Assessment Scale-cognitive subscale, ADAS-Cog), but the trial was not adequately powered to detect with statistical significance, an effect size smaller than 0.325 . In both studies, combination therapy with memantine added to a ChEI was well-tolerated [16, 17].
In addition to the lack of power to detect effect sizes smaller than 0.325, two possible explanations were provided by Porsteinsson and colleagues for the discrepancy in findings between MEM-MD-02 and MEM-MD-12: the difference in baseline disease severity, and the difference in permitted ChEIs . In the present study, data from both RCTs are combined, and the hypothesis that low power and baseline heterogeneities caused the divergent results between MEM-MD-02 and MEM-MD-12, and potentially obscured significant memantine treatment-related benefits in patients with moderate AD, is tested. In a post hoc meta-analysis and subgroup analysis approach, these data are used to assess the efficacy of memantine 20 mg/day versus placebo in patients receiving stable doses of donepezil (10 mg/day) in two subgroups: moderate to severe AD (MMSE 5 to 19), and moderate AD (MMSE 10 to 19).
The rationale for choosing these patient subgroups (subpopulations) were that they represent the current approved indication of memantine in the EU (moderate to severe AD), and the overlap of the approved memantine and donepezil indications in the EU (moderate AD). As is commonly done in clinical trials, the MMSE was used as a subpopulation staging surrogate measure to delineate mild (MMSE ≥ 20) from moderate (MMSE 10 to 19) and severe (MMSE < 10) stages of AD. Finally, since donepezil was the most commonly used ChEI in these trials, ChEIs other than donepezil were excluded, and analysis was restricted to patients receiving 10 mg/day of donepezil to minimise heterogeneity and any potential effects of underdosing.
Therefore, the analyses in this study of patients with AD with MMSE < 20 taking stable donepezil 10 mg/day consist of: 1) meta-analyses to compare the efficacy of memantine versus placebo across individual domains of AD; 2) pooled analyses to compare the efficacy of memantine versus placebo in reducing the occurrence of marked clinical worsening, and 3) pooled analyses to assess the tolerability profile of memantine versus placebo.