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Alzheimer's disease assessment scale-cognitive 11-item progression model in mild-to-moderate Alzheimer's disease trials of bapineuzumab.

ABSTRACT: Introduction:The objective of this study was to estimate longitudinal changes in disease progression (measured by Alzheimer's disease assessment scale-cognitive 11-item [ADAS-cog/11] scale) after bapineuzumab treatment and to identify covariates (demographics or baseline characteristics) contributing to the variability in disease progression rate and baseline disease status. Methods:A population-based disease progression model was developed using pooled placebo and bapineuzumab data from two phase-3 studies in APOE ?4 noncarrier and carrier Alzheimer's disease (AD) patients. Results:A beta regression model with the Richard's function as the structural component best described ADAS-cog/11 disease progression for mild-to-moderate AD population. This analysis confirmed no effect of bapineuzumab exposure on ADAS-cog/11 progression rate, consistent with the lack of clinical efficacy observed in the statistical analysis of ADAS-cog/11 data in both studies. Assessment of covariates affecting baseline severity revealed that men had a 6% lower baseline ADAS-cog/11 score than women; patients who took two AD concomitant medications had a 19% higher (worse) baseline score; APOE ?4 noncarriers had a 5% lower baseline score; and patients who had AD for a longer duration had a higher baseline score. Furthermore, shorter AD duration, younger age, APOE ?4 carrier status, and use of two AD concomitant medications were associated with faster disease progression rates. Patients who had an ADAS-cog/11 score progression rate that was not statistically significantly different from 0 typically took no AD concomitant medications. Discussion:The beta regression model is a sensible modeling approach to characterize cognitive decline in AD patients. The influence of bapineuzumab exposure on disease progression measured by ADAS-cog/11 was not significant. Trial Registration:ClinicalTrials.gov identifier: NCT00575055 and NCT00574132.

SUBMITTER: Samtani MN

PROVIDER: S-EPMC5975060 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Alzheimer's disease assessment scale-cognitive 11-item progression model in mild-to-moderate Alzheimer's disease trials of bapineuzumab.

Samtani Mahesh N MN Xu Steven X SX Russu Alberto A Adedokun Omoniyi J OJ Lu Ming M Ito Kaori K Corrigan Brian B Raje Sangeeta S Brashear H Robert HR Styren Scot S Hu Chuanpu C

Alzheimer's & dementia (New York, N. Y.) 20151009 3

<h4>Introduction</h4>The objective of this study was to estimate longitudinal changes in disease progression (measured by Alzheimer's disease assessment scale-cognitive 11-item [ADAS-cog/11] scale) after bapineuzumab treatment and to identify covariates (demographics or baseline characteristics) contributing to the variability in disease progression rate and baseline disease status.<h4>Methods</h4>A population-based disease progression model was developed using pooled placebo and bapineuzumab da ...[more]

PMID: 29854935

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Project description:BackgroundBapineuzumab, a humanized anti-amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer's disease.MethodsWe conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer's disease--one involving 1121 carriers of the apolipoprotein E (APOE) ε4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations.ResultsThere were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were -0.2 (P=0.80) and -1.2 (P=0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were -0.3 (P=0.64) and 2.8 (P=0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P=0.62) and 0.9 (P=0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE ε4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE ε4 allele carriers but not in noncarriers.ConclusionsBapineuzumab did not improve clinical outcomes in patients with Alzheimer's disease, despite treatment differences in biomarkers observed in APOE ε4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.).

Project description:BackgroundAlzheimer's disease (AD) is a globally prevalent neurodegenerative condition, clinically characterized by progressive memory loss and gradual impairment of cognitive functions. Bapineuzumab is a fully humanized monoclonal antibody that binds to neurotoxic amyloid proteins in the brain, enhancing their clearance. We performed this systematic review and meta-analysis to evaluate the safety and efficacy of bapineuzumab in patients with mild to moderate Alzheimer's disease.MethodsWe performed a web-based literature search of PubMed, Ovid, EBSCO, Scopus, Embase, Cochrane CENTRAL, and web of science using the relevant keywords. Data were extracted from eligible records and pooled as mean difference (MD) or risk ratio (RR) values with their 95% confidence interval (CI), using Review Manager software (version 5.3 for windows). Heterogeneity was measured by Chi-square and I-square tests.ResultThe pooled effect estimate from six randomized clinical trials (n = 2380) showed that bapineuzumab significantly reduced the cerebrospinal fluid concentration of phosphorylated tau proteins (Standardized MD = -5.53, 95% CI [-8.29, -2.76]). However, the bapineuzumab group was not superior to the placebo group in terms of change from baseline in Alzheimer's disease assessment scale (ADAS)-Cog11 (MD = 0.14, 95% CI [-0.72, 0.99]), disability assessment for dementia (DAD) scale (MD = 1.35, 95% CI [-1.74, 4.43]), and mini-mental state examination (MMSE) scores (MD = 0.08, 95% CI [-0.31, 0.47]). Regarding safety, bapineuzumab increased the risk of serious treatment-emergent adverse events (RR = 1.18, 95% CI [1.02, 1.37]) and cerebral vasogenic edema (RR = 40.88, 95% CI [11.94, 135.95]). All bapineuzumab doses (0.15, 0.5, 1, and 2 mg/kg) were similar to placebo in terms of change from baseline in ADAS-cog11, DAD, and MMSE scores, except for the 0.15 mg/kg dose, which caused a significant worsening on the ADAS-cog11 scale (MD = 5.6, 95% CI [0.22, 10.98]).ConclusionsConsidering the lack of clinical efficacy, combined with the significant association with serious adverse events, bapineuzumab should not be used to treat patients with mild to moderate AD. Future studies should investigate the effect of combining bapineuzumab with other therapeutic strategies and reevaluate the efficacy of targeting amyloid β proteins in AD therapy.

Project description:BACKGROUND:Development of new treatments for Alzheimer's disease (AD) has broadened into early interventions in individuals with modest cognitive impairment and a slow decline. The 11-item version of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) was originally developed to measure cognition in patients with mild to moderate AD. Attempts to improve its properties for early AD by removing items prone to ceiling and/or by adding cognitive measures known to be impaired early have yielded a number of ADAS-Cog variants. Using Alzheimer's Disease Neuroimaging Initiative data, we compared the performance of the 3-, 5-, 11- and 13-item ADAS-Cog variants in subjects with early AD. Given the interest in enrichment strategies, we also examined this aspect with a focus on cerebrospinal fluid (CSF) markers. METHODS:Subjects with mild cognitive impairment (MCI) and mild AD with available ADAS-Cog 13 and CSF data were analysed. The decline over time was defined by change from baseline. Direct cross-comparison of the ADAS-Cog variants was performed using the signal-to-noise ratio (SNR), with higher values reflecting increased sensitivity to detect change over time. RESULTS:The decline over time on any of the ADAS-Cog variants was minimal in subjects with MCI. Approximately half of subjects with MCI fulfilled enrichment criteria for positive AD pathology. The impact of enrichment was detectable but subtle in MCI. The annual decline in mild AD was more pronounced but still modest. More than 90 % of subjects with mild AD had positive AD pathology. SNRs were low in MCI but greater in mild AD. The numerically largest SNRs were seen for the ADAS-Cog 5 in MCI and for both the 5- and 13-item ADAS-Cog variants in mild AD, although associated confidence intervals were large. CONCLUSIONS:The possible value of ADAS-Cog expansion or reduction is less than compelling, particularly in MCI. In mild AD, adding items known to be impaired at early stages seems to provide more benefit than removing items on which subjects score close to ceiling.

Project description:BackgroundAlterations in circadian rhythms are present in the presymptomatic stage of Alzheimer's disease (AD), possibly contributing to its pathogenesis. However, it is unknown whether such alterations are associated with worse outcomes once individuals are diagnosed with symptomatic disease. We aimed to evaluate the association between the circadian rest-activity pattern and AD-related features in patients with mild-moderate AD.MethodsWe assessed the circadian rest-activity pattern of consecutive patients with mild-moderate AD through actigraphy for 14 days. Cerebrospinal fluid was obtained to determine the levels of important pathological markers including amyloid-beta protein (Aβ42), phosphorylated tau (P-tau), total tau (T-tau), and neurofilament light (NF-L). Neuropsychological evaluation was conducted at the beginning of the study and after 12 months of follow-up. Linear regression models were performed considering the global population and Aβ42+ patients only.ResultsThe cohort included 100 patients with mild-moderate AD. The median age [p25;p75] was 76.0 [73.0;80.0] years and 63.0% were female. Older age (effect size [SE] of 0.324 [0.096]; p = 0.001) and male sex (0.780 [0.193]; p = 0.001) were associated with increased fragmentation and decreased synchronization of the rhythm, respectively. After adjusting for age, sex, and season of the year, increased levels of T-tau (effect size [95% CI] of 0.343 [0.139 to 0.547]; p = 0.001) and NF-L (0.444 [0.212 to 0.676]; p = 0.001) were associated with a higher amplitude of the rest-activity rhythm. Increased fragmentation of the rhythm at baseline was associated with greater cognitive decline after one year of follow-up independent of age, sex, T-tau/Aβ42 ratio, educational level, and season of the year (- 0.715 [- 1.272 to - 0.157]; p = 0.013). Similar findings were obtained considering only the Aβ42+ patients.ConclusionsOur results suggest a potential role of the circadian rest-activity pattern in predicting the cognitive decline of patients with mild-moderate AD. Further studies are warranted to confirm these findings and to elucidate whether there is causality among the observed associations.

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Alzheimer's disease assessment scale-cognitive 11-item progression model in mild-to-moderate Alzheimer's disease trials of bapineuzumab.

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Alzheimer's disease assessment scale-cognitive 11-item progression model in mild-to-moderate Alzheimer's disease trials of bapineuzumab.

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