Of the 167 patients screened in the prerandomization period, 140 were randomized to the 4 groups (35, 35, 33, and 37 to placebo, 3mg, 5mg, and 10mg, respectively). In the randomization period, 1 patient in the placebo group was withdrawn before receiving the study drug due to refusal, and was excluded from the safety analysis set. Two patients (1 each in the placebo and 10mg groups) who did not meet probable DLB criteria and 2 patients (1 each in the placebo and 5mg groups) with no postbaseline efficacy assessments were excluded from the full analysis set. Thus, the safety analysis set included 139 patients (34, 35, 33, and 37 in the placebo, 3mg, 5mg, and 10mg groups, respectively), and full analysis set included 135 patients (32, 35, 32, and 36, respectively). Sixteen patients (4, 4, 2, and 6, respectively) withdrew during the study; LOCF was applied to them (). In the 10mg group, 3 patients discontinued during the titration phase: 1 at the 3mg/day and 2 at the 5mg/day period.
Patient disposition. SAS = safety analysis set.
Baseline patient characteristics are summarized in Table . The 4 groups were similar for demographic and disease-related characteristics, although significant differences were found in the distributions of women and men, and mean body weight. Because women predominated, mean body weight was lower in the 10mg group. Some patients were taking L-dopa, dopamine agonists, antidepressants, or benzodiazepines at baseline. However, the proportion of each medication was not different among groups. Baseline scores of the cognitive and behavioral scales were also comparable, although the mean NPI-10 score was lower in the 5mg group, and the WAIS-III symbol digit score was lower in the placebo group ().
Baseline Characteristics of Patients (Full Analysis Set)
Mean Changes in Clinical Variables from Baseline to Week 12 (Last Observation Carried Forward)
Mean changes in MMSE scores were significantly higher at the final evaluation (LOCF) in the 5 and 10mg groups (5mg, 3.4, p < 0.001; 10mg, 2.0, p = 0.001) than in the placebo group (−0.4; see Table , Fig ). When baseline values were adjusted as covariates, the difference between the 3mg and placebo groups was also significant. The results of the mixed-effect model analysis were consistent with those of LOCF analyses. The responder rate (MMSE change ≥3) was significantly higher in all donepezil groups (3mg, 42.9%, p = 0.013; 5mg, 65.6%, p < 0.001; 10mg, 44.4%, p = 0.007) compared to placebo (12.9%). No dose dependency was demonstrated on trend analysis. On the WMS-R attention/concentration and WAIS-III symbol digit tests, significant improvements were also noted in each dose group compared to placebo. No significant improvement was detected on the verbal fluency and visuoperceptual tests.
Mean changes from baseline in the (A) Mini-Mental State Examination and (B, C) Neuropsychiatric Inventory (B, NPI-10; C, NPI-2). Error bars represent standard deviation of the mean. LOCF = last observation carried forward.
Behavioral and Neuropsychiatric Symptoms
Scores for NPI-2 and NPI-4 were significantly more improved at the final evaluation (LOCF) in the 5mg (except NPI-4) and 10mg groups than in the placebo group (see Table , Fig ). When baseline values were adjusted as covariates, the difference in NPI-4 between the 5mg and placebo groups was significant. The difference in NPI-10 between each active group and placebo did not reach the significance level. The results of the mixed-effect model analyses were consistent with those of LOCF analyses. The trend analyses demonstrated a linear dose-dependent improvement for NPI-2 (linear, p = 0.036; 5mg saturation, p = 0.076) but not for NPI-4 and NPI-10.
The NPI-plus domains Delusion, Hallucination, and Cognitive Fluctuation improved in all active groups, whereas they deteriorated in the placebo group (Fig ). The differences between the placebo and both the 5 and 10mg groups were significant (5mg, p = 0.012, 0.014, and 0.004; 10mg, p = 0.002, <0.001, and <0.001 for each symptom, respectively).
Mean changes (95% confidence intervals) of individual Neuropsychiatric Inventory items.
The distributions of CIBIC-plus at the final evaluation (LOCF) in all active groups were significantly superior to that of placebo (p < 0.001 for each group; Table ). The responder rates were 33.3%, 68.8%, 71.0%, and 64.3% in the placebo, 3mg, 5mg, and 10mg groups, respectively. The differences from placebo were significant in the 3 and 5mg groups (3mg, p = 0.010; 5mg, p = 0.004; 10mg, p = 0.034). No dose dependency was demonstrated on trend analysis.
Distribution of the Clinician’s Interview-Based Impression of Change plus Caregiver Input at Week 12 (Last Observation Carried Forward)
ZBI score was reduced significantly more in the 10mg group than in placebo at the final evaluation (LOCF; p = 0.004), although the difference did not reach the significance level after baseline value adjustment (see Table ).
AEs were reported in 71%, 69%, 82%, and 87%, respectively, of the placebo, 3mg, 5mg, and 10mg groups (Table ). The majority were mild or moderate. The most common AE was elevated creatinine kinase (5.9%, 14.3%, 9.1%, and 13.5%, respectively). Cholinergic AEs such as diarrhea, nausea, anorexia, and abdominal discomfort were reported in some patients; however, no difference in incidence was noted between the placebo and any donepezil groups. Adverse parkinsonian events were reported in 2.9%, 8.6%, 12.1%, and 2.7%. The mean UPDRS part III score somewhat improved in all active groups at the final evaluation, whereas the score worsened in placebo, although the differences among groups did not reach the significance level (see Table ). Adverse behavioral events were 11.8%, 22.9%, 15.2%, and 8.1% in the placebo, 3mg, 5mg, and 10mg groups, respectively; nevertheless, these differences were not statistically significant. The proportions of AEs leading to withdrawal were similar between groups: 11.8%, 8.6%, 3.0%, and 8.1%, respectively. Serious AEs occurred in 5.9%, 5.7%, 6.1%, and 10.8% of the respective groups. Of these, only 2 events, agitation in the placebo group and subarachnoid hemorrhage in the 3mg group, were judged to be related to the study drug. One serious AE in the 10mg group (worsening of hallucinations) occurred while the patient was still taking 3mg/day during the titration period. There were no clinically relevant differences in vital signs or electrocardiogram between the groups.
In the present study, we found that donepezil improved both cognition and behavior in patients with DLB compared to placebo. Patients given 5 or 10mg donepezil showed greater improvement in the majority of the cognitive and behavioral measures, including the MMSE and NPI. Donepezil treatment also led to improved global function and reduced caregiver burden in this population. Because consistent improvements in many different measures across broad domains were observed, despite the exploratory nature of this study due to several limitations as discussed below, we believe that our findings demonstrated encouraging effects of donepezil for patients with DLB.
The majority of cognitive measures showed significant between-group differences. In particular, there was an apparent improvement in overall cognitive function, especially with the higher 2 doses; the mean changes in MMSE score favored donepezil by 2.0 to 3.8 points. This difference was larger than that reported in other studies of ChEIs in DLB, AD, and Parkinson disease with dementia (PDD).15, 32, 33
Improvement was also noted in the attentive-executive domains. We presume that a ceiling effect caused the nonsignificant outcome in the visuoperceptual domain.
Also noteworthy was the improvement of neuropsychiatric features and reduction of caregiver burden in the donepezil groups. The beneficial effect of donepezil was evident on each symptom domain characteristic of DLB (delusion, hallucination, and cognitive fluctuation), as generally consistent with the previous rivastigmine study15
except for apathy. For NPI-2, a linear dose-response relationship was demonstrated. Caregiver burden also was reduced significantly at the highest dose, 10mg/day.
Patients who received donepezil also demonstrated improved global function, as measured by CIBIC-plus. A higher percentage of patients showed improvement, and fewer patients worsened in each donepezil group than in placebo. The beneficial effect seemed greater than those of ChEIs reported for patients with AD and PDD.33-35
In a trial of rivastigmine for PDD, improvement of activities of daily living, which would reflect treatment-induced changes in cognitive, behavioral, and motor symptoms, was reported.33
Such an outcome may also be useful to compare the clinically meaningful impacts of the treatment among trials.
AEs were not rare; however, only approximately 8% of the study population withdrew due to AEs, and the prevalence of withdrawal or AEs, including typical cholinergic side effects, did not differ among treatment groups. Although symptoms of parkinsonism were reported as AEs somewhat more frequently in the 3 and 5mg groups than in the placebo group, the difference was not reflected in the mean UPDRS part III score. Indeed, the score demonstrated numerical, although nonsignificant, improvement in the highest dose group. Cholinergic treatment theoretically exacerbates parkinsonism. However, the possible beneficial effects of donepezil observed in this study suggest that the use of ChEIs should not necessarily be avoided in the treatment of DLB due to concern of possible parkinsonism. These unexpected effects, despite not being confirmed, might be explained by a complicated neuronal network for motor control.
As the discontinuation rate was relatively low, and there was no significant difference among groups, it is unlikely that exclusion bias caused by early termination affected the efficacy results. Both the LOCF analysis and the mixed-effect model analysis consistently showed favorable results.
As an aim of this study was to explore targetable clinical presentations of DLB, we did not set a specific primary endpoint despite assigning multiple efficacy outcome measures, which could be a major limitation. In addition, cognitive fluctuation was measured by an unestablished tool, which is well equipped but not yet validated. Another limitation is that nearly half of the centers enrolled only 1 or 2 patients, which may have caused an inter-rater discordance of the clinical ratings, although a training and certification course was mandatory for the investigators. Also, the small sample, short duration of treatment, and lack of formal dose-response comparison are evident limitations. Nevertheless, the results of this study strongly suggest that donepezil is safe in patients with DLB, and provide a preliminary indication of its clinical effectiveness in terms of cognitive function, behavioral symptoms, and global function of DLB, and consequently in effecting a reduction of caregiver burden. The findings of the present study with donepezil should be verified in a confirmatory clinical trial. In addition, long-term effects should be examined. Although both 5mg/day and 10mg/day seemed to be beneficial, 10mg/day was somewhat more beneficial in terms of behavioral symptoms. The optimum dose should be determined in a follow-up trial, in which dose titration with patients unable to tolerate 10mg/day being allowed to take 5mg/day would be a sensible design.