This pooled AUC analysis of data from over 1,400 patients from four RCTs in moderate to severe AD provides robust support for the view that, over the course of six months, adding memantine to stable donepezil therapy results in cumulative multi-domain benefits that are superior to monotherapy with either drug. In addition, our data suggest that, for all four clinical domains examined (cognition, daily functioning, behavior, global clinical status), the protocol-specified snapshot analysis underestimates the benefits of combination or monotherapy, or both, compared with the assessment of cumulative effects using the AUC method. Finally, the results indicated that benefits of combination therapy, compared to individual monotherapies, are additive, but not synergistic.
Results from both the primary AUC analysis and the secondary comparative MMRM analysis extend previous evidence from randomized trials that adding memantine to stable background donepezil treatment in patients with moderate or severe AD is associated with significant clinical benefits over adding placebo [5,7] by demonstrating that memantine-donepezil combination is superior to both component monotherapies, and that, as expected, donepezil and memantine monotherapies are superior to no active treatment (placebo) [9,28]. Those findings are also in agreement with long-term, prospective observational cohort studies (three to four years or longer) that support the benefits of ChEI-memantine combination therapy over monotherapy, and monotherapy over no treatment [9,28,29]. Our analysis quantifies the cumulative aspect of the combination therapy benefits and suggests that they continue accumulating through the end of the six-month study period, both in individual domains, and overall, as measured using the 4D-CI.
The results also extend previous findings by quantifying, in a readily interpretable manner for clinicians and caregivers, the magnitude of treatment benefits over the absence of active treatment (Table 3). For example, it is clinically useful to be able to discuss with patients and caregivers that, on average, over a period of six months, patients who were treated with placebo continued to decline overall on a composite measure of cognition, function, behavior and global status, whereas, relatively speaking, those treated with the memantine-donepezil combination accrued benefits of up to 450%, depending on the clinical characteristic studied, or to discuss that adding memantine to stable background treatment with donepezil could improve an overall cumulative benefit by approximately 50% (Table 3).
While the AUC and 4D-CI results clearly support the ordinal benefits of monotherapy and add-on combination therapy relative to the detrimental effects of non-drug treatment (that is, treatment with placebo only), the benefits of monotherapies relative to each other are less differentiated. In the snapshot baseline-to-endpoint and the visit-by-visit changes from baseline analyses, donepezil-placebo treatment produced significantly larger effects on the SIB (cognitive measure) than memantine monotherapy (Figure 1). In contrast, no difference was observed in the 0 to 24 week AUC analysis and a small, but significant, difference in favor of donepezil-placebo treatment was observed in the 18 to 24 week-interval weekly AUC analysis. These results could indicate a signal of greater relative effect on cognition for donepezil compared to memantine monotherapy. However, there is a caveat to this observation due to the clinically small but statistically significant differences in baseline MMSE score and age, observed in the two trials of memantine monotherapy: the mean baseline MMSE score in the MRZ-90001-9605 study was approximately two points lower than in the other studies, and the mean age at baseline in the MEM-MD-01 study was approximately two years older than the other studies. While the analyses adjusted for statistically significant baseline differences and baseline-by-age interactions, these clinically small differences preclude us from making final conclusions regarding any potential differential cognitive effect of donepezil versus memantine monotherapy in this population.
Assessments based on changes from baseline at a single time point are bound to obscure the longitudinal aspects of treatment effects and ignore most information regarding the emergence, onset, duration, and variability of symptoms or disease characteristics [19]. In our analysis, for example, score or score change trajectories over time for all four outcome measures were not linear (Figures 1C, 2C, 3C and 4C), and a simple baseline-to-endpoint assessment would falsely assume that they were, thereby leading to potentially inaccurate estimates of treatment effects. This suggests that the AUC method would be a more robust tool for analyzing non-linear clinical data. In addition, the AUCs are intuitive, straightforward to implement, and maintain the direction of improvement of each individual scale. When calculated at the patient level, they represent each individual’s summary of change for a given period of time (as opposed to change at a given time point) and can be treated as raw data for statistical analyses.
Similarly, use of composite indices may be associated with several advantages compared with analyzing data from different clinical domains separately. For example, a pre-specified composite index could be a more ecologically valid [30] way of capturing change in a condition as complex as AD [15], and it could simplify the problem of choosing one or two primary efficacy parameters from tools designed to assess individual clinical domains. This, in turn, could reduce the need for multiple hypothesis testing: researchers could prospectively create a composite index that best addresses their key experimental question and only perform secondary analyses for questions of secondary importance.
Study strengths
This analysis represents the largest pool to date of patients with moderate to severe Alzheimer’s dementia (N = 1,408) treated in rigorous RCTs. The study also utilized robust analytics methods (MMRM, ANCOVA) to compare the Snapshot (baseline-to-endpoint) and AUC approaches. The AUC method has the potential to ‘smooth the data’ of patients whose visit-by-visit scores are prone to variations, thereby potentially increasing the signal-to-noise ratio. Additionally, combining the AUC approach with the 4D-CI extends the smoothing effect across four critical clinical domains and allows for integration of various clinical assessments over time into a single numerical value. By potentially lowering noise stemming from variance, such a composite representation would have the advantage of capturing treatment-related effects more robustly, and with higher power. Finally, the relative effect estimates (Table 3) allow for intuitive and meaningful interpretations of clinical-trial data.
Study limitations
Excluding patients with background ChEI treatment other than donepezil may reduce external validity and generalizability of results. Another potential limitation, which applies to the individual pooled trials as well, involves use of MMSE as a key criterion for study enrollment. That measure assesses cognition only —just one of several AD domains— and it does so in a limited fashion, particularly in patients with high education and intellectual abilities. Finally, in clinical practice, patients are usually treated for periods longer than the six-month duration of trials pooled for the purpose of this analysis, which emphasizes the necessity of obtaining Level II evidence from long-term observational clinical cohort studies in order to better delineate the long-term risk–benefit calculus of therapies to patients and to society, and to better guide therapeutic discovery efforts [10,28,29].
Clinical recommendations and future directions
Based on these results, which add to the preponderance of clinical evidence [5-12] that memantine add-on-to-donepezil/ChEI combination therapy is superior to component monotherapies and that non-treatment is associated with significant decline over six months, it is our clinical recommendation that, barring any contraindication, all individuals in the moderate or severe stages of AD dementia receive combination treatment. However, this study does not inform regarding when anti-AD medications should be stopped; there is a dearth of data to inform regarding this very important aspect of AD management that requires further study.
Finally, a recent FDA draft guidance suggested that the composite Clinical Dementia Rating scale Sum-of-Boxes score be used as the primary outcome measure in pivotal clinical trials involving individuals with mild cognitive impairment due to AD or prodromal AD [31,32]. Our AUC 4D-CI analysis, due to its ability to capture both the clinical trajectory and a four-dimensional picture of illness, should be investigated in future studies as a potential candidate outcome measure for inclusion in AD clinical trials.