E. Whalen

A Randomized, Double‐Blind, Placebo‐Controlled Study of the Efficacy and Safety of Donepezil in Patients with Alzheimer's Disease in the Nursing Home Setting

OBJECTIVES: To evaluate the safety and efficacy of donepezil in the management of patients with Alzheimers disease (AD) residing in nursing home facilities.

Efficacy of donepezil on behavioral symptoms in patients with moderate to severe Alzheimer's disease.

OBJECTIVE This subanalysis of a large, double-blind, placebo-controlled trial examined the prevalence of behavioral symptoms in moderate to severe Alzheimers disease (AD), and the effect of treatment with donepezil. METHODS Two hundred ninety patients with moderate to severe AD (standardized Mini-Mental State Examination scores 5-17) were randomized to receive 24 weeks of once-daily doses of donepezil 5 mg/day for 28 days, and 10 mg/day thereafter per the clinicians judgment (n = 144), or placebo (n = 146). The outcome measure of interest was the 12-item Neuropsychiatric Inventory (NPI). RESULTS Baseline demographics were similar between the treatment groups. Least squares mean (+/- SE) baseline NPI 12-item total scores were 19.55 +/- 1.48 and 19.30 +/- 1.45, respectively. At baseline, the most common symptoms were apathy/indifference (67%), aberrant motor behavior (53%), depression/dysphoria (52%), anxiety (49%), and agitation/aggression (45%). NPI individual item change from baseline scores at Week 24 using a last observation carried forward (LOCF) analysis showed benefits with donepezil treatment compared with placebo for all items, with significant treatment differences for depression/dysphoria, anxiety, and apathy/indifference (p < .05). Symptoms present at baseline that improved significantly for donepezil- compared with placebo-treated patients at Week 24 LOCF included anxiety, apathy/indifference, and irritability/lability (p < .05). When patients who were not receiving psychoactive medications at baseline were analyzed separately, significant improvements in NPI (continued) 12-item total score were observed with donepezil compared with placebo at most visits and at Week 24 LOCF (p < .05). CONCLUSIONS Behavioral symptoms of the magnitude observed in this moderate to severe AD population improved with donepezil.

A comparison of pregabalin, lamotrigine, and placebo as adjunctive therapy in patients with refractory partial-onset seizures.

PURPOSE This study assessed the comparative efficacy of pregabalin for refractory partial seizures. METHODS Four-hundred and thirty-four patients with partial seizures were randomized to pregabalin, lamotrigine, or placebo as adjunctive therapy for 17 weeks of double-blind treatment. In phase I (11 weeks), pregabalin was titrated over 1 week and lamotrigine over 5 weeks to fixed dosages of 300mg/day for both. In phase II (6 weeks), patients not yet seizure-free were increased to pregabalin 600mg/day or lamotrigine 400mg/day. RESULTS During phase I, there was a nonsignificant trend toward a greater reduction in seizures with pregabalin versus placebo and lamotrigine. Across the 17 weeks of treatment, pregabalin showed a median percentage reduction from baseline in seizure frequency of -20.0% (p=.001) versus placebo, and -9.7% (p=.080) versus lamotrigine. The responder rate (> or =50% reduction in seizure frequency) for pregabalin exceeded that of placebo (36% vs 21%; p=.007) and lamotrigine (36% vs 24%; p=.04). Adverse events were consistent with the known safety profiles of pregabalin and lamotrigine. DISCUSSION Pregabalin was demonstrated to be noninferior to lamotrigine in the treatment of refractory partial seizures. Overall conclusions were complicated by an unusually large and heterogeneous placebo response.

A Comprehensive Drug Safety Evaluation of Pregabalin in Peripheral Neuropathic Pain

Pregabalin is a commonly used therapy currently recommended as first‐line treatment for a number of neuropathic pain (NeP) conditions. Since licensure, a number of clinical trials of pregabalin in different NeP conditions have been completed from which additional data on safety and tolerability can be drawn. In this analysis, patient‐level data from 31 randomized clinical trials of pregabalin in peripheral NeP sponsored by Pfizer were pooled and assessed for incidence of adverse events (AEs). Incidence by age, disease condition, and race, together with risk differences and time to onset and resolution of AEs, was assessed. In total, 7,510 patients were included: 4,884 on pregabalin (representing 805 patient‐years treatment) and 2,626 on placebo. Pregabalin vs. placebo risk analysis identified 9 AEs with a risk difference, for which the lower limit of the 95% confidence interval (CI) was > 1%: dizziness (risk difference [95% CI]: (17.0 [15.4 to 18.6]), somnolence (10.8 [9.5 to 12.1]), peripheral edema (5.4 [4.3 to 6.4]), weight increase (4.7 [3.9 to 5.5]), dry mouth (2.9 [2.1 to 3.8]), constipation (2.3 [1.5 to 3.2]), blurred vision (2.2 [1.6 to 2.9]), balance disorder (2.0 [1.5 to 2.5]), and euphoric mood (1.6 [1.2 to 2.0]). The most common AEs, dizziness and somnolence, typically emerged within the first 1 to 2 weeks of treatment and resolved 1 to 2 weeks later, without resulting in cessation of treatment. The data from this review provide information, indicating which AEs may be expected in patients treated with pregabalin, and suggest that careful dose titration to the highest tolerable dose is the most appropriate approach in clinical practice.

Generating productive dialogue between consulting statisticians and their clients in the pharmaceutical and medical research settings

Due to the ever-increasing complexity of scientific technologies and resulting data, consulting statisticians are becoming more involved in the design, conduct, and analysis of biomedical research. This requires extensive collaboration between the consulting statistician and nonstatisticians, such as researchers, clinicians, and corporate executives. Consequently, a successful consulting career is becoming ever more dependent on the statisticians ability to effectively communicate with nonstatisticians. This is especially true when more complex, nontraditional analytical methods are required. In this paper, we examine the collaboration between statisticians and nonstatisticians from three different professional perspectives. Integrating these perspectives, we discuss ways to help the consulting statistician generate productive dialogue with clients. Finally, we examine how universities can better prepare students for careers in statistical consulting by incorporating more communication-based elements into their curriculum and by offering students ample opportunities to collaborate with nonstatisticians. Overall, we designed this exercise to help the consulting statistician generate dialogue with clients that results in more productive collaborations and a more satisfying work experience.

DONEPEZIL FOR NURSING HOME PATIENTS WITH DEMENTIA: A REINTERPRETATION OF THE EVIDENCE - Response to the Editor

To the Editor: We read with interest Tariot et al.’s recent study examining the effect of donepezil in nursing home residents with Alzheimer’s disease 1 and believe that the authors’ discussion of the results was overly enthusiastic about findings favoring the use of donepezil and excessively dismissive of findings that should give evidencebased practitioners reason to pause. First, the authors report no significant differences between donepezil and placebo for the primary endpoint of behavioral problems, as measured by the neuropsychiatric inventory (NPI). Although the authors argue that the negative finding may be an artifact of “uncontrolled methods of behavior management” in the nursing home (apparently the usual pharmacological and nonpharmacological care for patients with behavioral disturbances), this explanation is unconvincing. Either way, one would be hard pressed to support the use of donepezil if reasonable alternative approaches (especially nonpharmacological care for behavior disturbances) rendered its use irrelevant. In a series of additional analyses, the authors examined the effect of donepezil on each of the 12 behaviors measured by the NPI. Although there was a trend toward worse outcomes for 11 of the 12 behaviors, the discussion focused only on the one behavior favoring donepezil. Given the testing of multiple hypotheses, it is not surprising that one of these analyses would favor donepezil by chance. The discussion of this isolated finding should have been more cautious in light of the number of statistical tests applied and the contradictory findings for the other 11 behavioral outcomes. The discussion puts considerable emphasis on the moderate improvement in clinical dementia rating scores and early differences in Mini-Mental State Examination (MMSE) scores in donepezil-treated patients. However, it appears that by the end of the study the differences in MMSE scores had disappeared, although no Pvalue is presented to clarify this. Given the last observation carried forward methodology, the discussion should have focused primarily on differences at the final study visit, with differences at other time points viewed as tertiary outcomes. In addition, the authors are too quick to dismiss the lack of benefit in activities of daily living—an important metric for patients and caregivers. The explanations for the lack of effect seem post hoc. Finally, the discussion of adverse events should have been more cautious. The substantial difference in the incidence of weight loss between donepezil and placebo (19% vs 10%) is particularly troubling. Although the Pvalue for this difference is not reported in the paper, we calculate it to be statistically significant ( P . 05). The mean weight loss of 3 kg in patients suffering this adverse event is clinically important and can initiate a cascade of other problems leading to functional decline and worsening quality of life. Clinicians must seriously balance this adverse effect against any potential effect on cognitive function. In sum, this study shows no evidence of benefit in the treatment of behavioral problems in nursing home patients with dementia. Secondary measures of cognitive and daily function are mixed and do not provide convincing evidence of substantial benefit in patients with the most severe cognitive impairment. Furthermore, the higher rates of potentially serious adverse events such as weight loss are troubling. Clinicians should be cautious in using donepezil for nursing home patients with dementia.

GETTING DONEPEZIL INTO THE NURSING HOME ‐ Response to the Editor

Even more eye catching is the assertion that, “at the very least, the data in this trial demonstrate that cognition and overall dementia severity are maintained for 6 months.” At 6 months, the cognitive measure, the main outcome measure, and the ADL measure were not significantly different from placebo. There is no evidence of stabilization. The drug makers supported four of the seven authors in this study and have paid them consulting fees and honoraria. The other three authors are full-time employees of the drug company. This article represents a failure of peer review.