Disease Stage in Alzheimer Disease and Treatment Effects of Rivastigmine

309

216

(2: 2:2: 1) to once-daily placebo, 2 mg RSG XR, 8 mg RSG XR or 10 mg donepezil (control). Coprimary endpoints were change from baseline to week 24 in the Alzhei mer's Disease Assessment Scale-cognitive subscale (ADAS-Cog) score, and week 24 Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+). Results: At week 24, no significant differences from placebo in change from baseline in coprimary endpoints were detected with either the RSG XR dose in APOE-4 -negative subjects or overall. For donepezil, no significant treatment difference was detected in ADASCog; however, a significant difference was detected (p = 0.009) on the CIBIC+. Peripheral edema was the most common adverse event for 8 mg RSG XR (15%) and placebo (5%), and nasopharyngitis for 2 mg RSG XR (7%). Conclusion: No evidence of efficacy of 2 mg or 8 mg RSG XR monotherapy in cognition or global function was detected in the APOE-4 -negative or other analysis populations. The safety and tolerability of RSG XR was consistent with its known pharmacology.Copyright © 2010 S. Karger AG, Basel Key WordsRosiglitazone, extended release ؒ Monotherapy ؒ Alzheimer's disease ؒ Peroxisome proliferator-activated receptor-␥ ؒ Cognition ؒ Apolipoprotein E allele 4 ؒ Health outcomes ؒ Donepezil Abstract Background/Aims: A phase II study of the peroxisome proliferator-activated receptor-␥ agonist rosiglitazone extended release (RSG XR) in mild-to-moderate Alzheimer's disease (AD) detected a treatment benefit to cognition in apolipoprotein E ( APOE )-4 -negative subjects. The current phase III study with prospective stratification by APOE genotype was conducted to confirm the efficacy and safety of RSG XR in mild-to-moderate AD. An open-label extension study assessed the long-term safety and tolerability of 8 mg RSG XR. Methods: This double-blind, randomized, placebo-controlled study enrolled 693 subjects. Within 2 APOE allelic strata ( 4 -positive, 4 -negative), subjects were randomized

Section: Discussionsupporting

confidence: 65%

Rosiglitazone Monotherapy in Mild-to-Moderate Alzheimer’s Disease: Results from a Randomized, Double-Blind, Placebo-Controlled Phase III Study

Gold

Alderton

Zvartau-Hind

et al. 2010

309

216

“…Analyses of worsening of clinical symptoms have previously been reported by Kurz et al [23] and Raskind et al [24] examining the effects of rivastigmine, however, the analyses were restricted to single domains only. Analyzing single domains increases the risk of erroneously identifying fluctuation in test performance as treatment effect and disregarding deterioration in another domain.…”

Section: Discussionmentioning

confidence: 99%

“…The 23-item version, ADCS-ADL 23 , was used in the studies including mild to moderate AD patients. The 19-item version, ADCS-ADL 19 , which was specifically developed for moderate to severe AD patients [22] , was used in the studies including moderate to severe AD patients.…”

Section: Outcome Measuresmentioning

confidence: 99%

Analysis of the Effect of Memantine in Reducing the Worsening of Clinical Symptoms in Patients with Moderate to Severe Alzheimer’s Disease

Wilkinson

Andersen

2007

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and delaying disease worsening is a relevant treatment outcome. Methods: Data from 6 randomized, double-blind, placebo-controlled, 6-month studies were pooled and a subgroup of patients (867 on placebo, 959 on memantine) with moderate to severe AD (Mini- Mental State Examination <20) was analyzed. ‘Any clinical worsening’ was defined as a decline on the Alzheimer’s Disease Assessment Scale – Cognitive Subscale (ADAS-cog) or the Severe Impairment Battery (SIB) and on the Clinician’s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-plus) and the Alzheimer’s Disease Cooperative Study – Activities of Daily Living Inventory (ADCS-ADL), and ‘marked clinical worsening’ as ≧4 points decline on the ADAS-cog or ≧5 points on the SIB and decline on the CIBIC-plus and the ADCS-ADL. Results: More placebo-treated than memantine-treated patients showed any clinical worsening (28 vs. 18%; p < 0.001), and 21% placebo-treated patients compared to 11% memantine-treated patients had marked clinical worsening (p < 0.001). Conclusion: In this population of moderate and severe AD patients, treatment with memantine was associated with reducing worsening of clinical symptoms in AD during the 6-month study period.

“…If ChEI treatment can slow or stabilize the expected decline this could represent a clinical benefit [37] . The issue of heterogeneity of response has with few exceptions [38][39][40] not often been addressed in most of the second generation ChEI trials but was observed and discussed in the tacrine trials [41] . We could demonstrate a heterogeneity of response in this study simply by describing the MMSE and the ADAS-cog change in the three different global response groups defined by the CIBIC score.…”

Section: Discussionmentioning

confidence: 99%

Donepezil in Alzheimer’s Disease: What to Expect after 3 Years of Treatment in a Routine Clinical Setting

Wallin

Andreasen

Eriksson

et al. 2006

Background/Aims: Clinical short-term trails have shown positive effects of donepezil treatment in patients with Alzheimer’s disease. The outcome of continuous long-term treatment in the routine clinical settings remains to be investigated. Methods: The Swedish Alzheimer Treatment Study (SATS) is a descriptive, prospective, longitudinal, multicentre study. Four hundred and thirty-five outpatients with the clinical diagnosis of Alzheimer’s disease, received treatment with donepezil. Patients were assessed with Mini-Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), global rating (CIBIC) and Instrumental Activities of Daily Living (IADL) at baseline and every 6 months for a total period of 3 years. Results: The mean MMSE change from baseline was positive for more than 6 months and in subgroups of patients for 12 months. After 3 years of treatment the mean change from baseline in MMSE-score was 3.8 points (95% CI, 3.0–4.7) and the ADAS-cog rise was 8.2 points (95% CI, 6.4–10.1). This is better than expected in untreated historical cohorts, and better than the ADAS-cog rise calculated by the Stern equation (15.6 points; 95% CI, 14.5–16.6). After 3 years with 38% of the patients remaining, 30% of the them were unchanged or improved in the global assessment. Conclusion: Three-year donepezil treatment showed a positive global and cognitive outcome in the routine clinical setting.