The effects of 24 weeks of treatment with 2-mg or 8-mg RSG XR monotherapies on cognition and global function in APOE-4
-negative subjects were not statistically or clinically different from placebo. In a previous exploratory analysis of RSG XR monotherapy in mild-to-moderate AD, a treatment-by-genotype interaction was detected for change from baseline versus placebo in ADAS-Cog score at week 24 and in week 24 CIBIC+ score [23
]. In that study, ADAS-Cog treatment differences ranged from −2.3 to −2.9 across RSG XR doses (2, 4, 8 mg) in APOE-4
-negative subjects, and trends toward improvements in this genetic subgroup were also observed on CIBIC+. In contrast, no beneficial effects of RSG XR were observed in APOE-4
-positive subjects or in the overall ITT population. In this larger study, which was prospectively designed to enable rigorous assessment of changes in ADAS-Cog and CIBIC+ scores in the total study population and in APOE 4
subgroups, there was adequate power to enable detection of modest effects, and the findings from the exploratory study were not replicated. The SD of the treatment differences and the dropout rate were consistent with the sample size calculations.
A donepezil treatment group was included in this study as an active control. Since there was no expectation for an interaction between the standard recommended daily dose of donepezil and APOE
allele status, analysis for this group was powered at the main effect level (full ITT population). Significant efficacy versus placebo was not detected for ADAS-Cog performance in the full ITT donepezil-treated population, a result that was unexpected based on previous donepezil trial outcomes in the mild-to-moderate AD population [38
]. However, a significant effect was detected with donepezil on CIBIC+ scores at 24 weeks in the full ITT population as well as in the all-except-4/4
subgroup, although for both groups, the improvement was less robust than that seen in prior donepezil studies [38
]. Nevertheless, the CIBIC+ outcomes in the donepezil control analysis suggest that the assay sensitivity was adequate to allow interpretation of the RSG XR versus placebo differences. Also in support of the assay sensitivity, ADAS-Cog values in the placebo group showed that the mean scores declined over time (as expected), although the magnitude of the decline was slightly smaller than reported in historical studies with ChEI [38
The first step in the testing hierarchy (8 mg versus placebo in the APOE-4
-negative group) (fig. ) did not fulfill the statistical requirements for significance. Analysis results for the other prospectively defined subgroups (full ITT and all-except-4
populations) are reported for completeness, but should be considered exploratory. No efficacy was identified for either RSG XR dose in the analyses of the all-except-4/4
group or full ITT population. The effects of RSG XR were evaluated in the population that excluded the homozygote group (i.e. in the all-except-4/4
group) since a potential for slower disease progression in 4/4
homozygotes has been reported [43
]. The results for the all-except-4/4
group, which comprised 90% of the population in this study, were very similar to those for the full ITT population, indicating that 4
homozygous status did not affect outcomes in our sample.
The ADAS-Cog may be more sensitive to disease progression and treatment effects in moderate versus mild AD [46
], and a post hoc analysis was performed to analyze whether treatment effects in this study differed by baseline MMSE scores (i.e. in subjects with moderate versus mild AD). For 2 mg RSG XR versus placebo, the treatment effect was similar and nonsignificant for both subjects with mild (MMSE score ≥18) and more moderate (MMSE score <18) AD; however, for 8 mg RSG XR and donepezil, the ADAS-Cog treatment benefit in the moderate AD subgroup was numerically greater than that in the mild subgroup. No clear differences were detected in the magnitude of effects for CIBIC+ scores between mild and moderate subgroups. Since group sizes were reduced for this analysis and lacked statistical power, caution is needed in interpreting these findings. Nevertheless, this finding is consonant with results from studies with other agents showing that the ADAS-Cog has greater sensitivity to detect cognitive decline and treatment effects in moderately severe versus milder AD [47
Although a correlation between cognitive performance and markers of glycemia in patients with DM has been identified in numerous studies [50
], correlations between cognition and glucose control in AD regardless of diabetic status are poorly defined [51
]. Our post hoc analysis detected no correlation between ADAS-Cog performance and baseline glucose or HbA1c levels. It should be noted that our analysis of glucose levels was limited because no fasting samples were collected in this study.
RSG XR monotherapy was generally well tolerated during 24 weeks of treatment in this study. The most common AE reported in the RSG XR groups were consistent with the profile of RSG immediate release (IR) in T2DM [31
]. The proportion of subjects with AE was lower for 2 mg RSG XR compared with 8 mg RSG XR and was generally comparable across the APOE 4
subgroups and the full safety population.
As expected, the incidence of PPAR-γ-agonist-related AE was higher with RSG XR, although the rates were relatively low across treatment groups. The most noteworthy AE with RSG XR treatment were nasopharyngitis and hyperlipidemia at the 2-mg dose, and peripheral edema at the 8-mg dose; these were the most common AE, and the only AE occurring at a rate more than twice that for the placebo. The incidence of edema was not unexpected as fluid retention is a well-documented side effect of this class of hypoglycemic drugs, mediated by actions at PPAR-γ receptors in the renal collecting ducts by increases in vascular permeability and reduced systemic vascular resistance [53
]. The absolute incidence of AE of edema for RSG XR was consistent with that for RSG IR in patients with T2DM and with results from recent metabolic studies [36
]. The absolute difference between the 8-mg RSG XR and placebo groups in the incidence of edema was approximately 10%, which is consistent with previous reports on elderly subjects with T2DM [31
]. Interestingly, the incidence of edema in the placebo group (5%) was higher than that seen in previous studies. The higher absolute rates across all treatments may be due to closer surveillance, given an increasing level of education among clinicians related to the reporting of edema as an AE.
Other AE related to fluid retention (e.g. anemia, cardiac failure, acute cardiac failure), elevated transaminases, depression and bone fractures were uncommon at both RSG XR doses. It is noteworthy that not all investigators reported hyperlipidemia as an AE; therefore, the incidence of hyperlipidemia based on clinical laboratory data was higher than that reported as an AE. For the AE of dyslipidemia, reported in 5% of the subjects, associated laboratory values, relevant history and/or evidence of elevated baseline lipids were often lacking. In light of findings for hyperlipidemia in this study, laboratory data would likely provide a more consistent basis for determining the true incidence of dyslipidemia.
Mean changes in hematology and clinical chemistry parameters were generally small and comparable across treatments. Dose-dependent declines in hemoglobin levels, hematocrits and other cell counts observed in the RSG treatment groups were consistent with hemodilution [37
]. Dose-dependent increases in total cholesterol and low-density lipoprotein observed with RSG XR treatment were consistent with the known-effects profile of RSG IR in T2DM [31
]. A higher proportion of subjects in the RSG XR versus placebo or donepezil treatment groups experienced CK elevation greater than the ULN. The numbers of subjects across treatment groups with CK elevations of 2× ULN (1–4/group) and 3× ULN (0–1/group) were small, with no notable differences between groups. Changes in mean LDH levels were observed for both RSG XR doses, but shifts of potential clinical concern were similar to those for donepezil or placebo.
Although the duration of RSG exposure was lengthened during the open-label extension study, the safety profile was very similar to that in the 8-mg RSG XR dose group in the blinded REFLECT-1 study. The rates of treatment discontinuation were similar in the studies, and there were no major differences between APOE-4
-negative and APOE-4
-positive subjects in the overall incidence of SAE or AE, including AESI, during the study. In both studies, the most common AE overall, as well as the most common drug-related AE, was peripheral edema. Based on mean values, cognitive decline and slightly worse global change were evident during the open-label extension study. No differences in results were noted for any efficacy endpoint based on APOE 4
The limitations of this study include those inherent in investigations of AD: a limitation on treatment duration for a placebo-controlled study in a significantly ill population [36
]; variability in AD progression [56
], and the use of assessment tools that may be inadequate for detecting drugs with a modest treatment effect in a mild-to-moderate AD population [46
]. The ADAS-Cog was chosen as an assessment in this study, based on published outcomes for the active control donepezil, and on its widespread use in evaluating new therapies for AD. Our results for donepezil effects and the post hoc analysis by baseline severity were consistent with other reports, suggesting that the ADAS-Cog is most sensitive as a primary endpoint in more moderate AD populations. Another limitation may be that effective levels of RSG may not be achieved in target tissues in the brain since RSG is a substrate for the multidrug-resistant gene product permeability glycoprotein [22
]. In addition, evidence suggests that the permeability glycoprotein efflux transporter is upregulated in the presence of inflammatory cytokines [59
], raising the possibility that neuroinflammation common in AD could limit RSG exposure and obviate its potential benefit [60
]. A PPAR-γ with high penetration of the blood-brain barrier should be investigated to further evaluate the role of this class of agents in AD.
Although efficacy was not demonstrated with RSG treatment in this study, the abundance of data on the role of underlying metabolic disorders remains of central concern in AD, and agents such as RSG, which modify insulin sensitivity, remain as therapeutic options worthy of further inquiry. This study illustrates approaches to managing the complexities of AD clinical trials and the measures needed to recruit optimal control groups, such as incorporating genetic stratification and a donepezil-treated positive control arm. However, cognitive instruments that are more sensitive to cognitive decline in mild AD are required for studies of short duration.