Dataset Information

Size of the treatment effect on cognition of cholinesterase inhibition in Alzheimer's disease.

ABSTRACT:

Background

Six cholinesterase inhibitors (ChEIs) have been tested in people with Alzheimer's disease, using methods currently required for regulatory approval. The clinical importance of their treatment effects is controversial.

Objective

To determine whether cholinesterase inhibition produces treatment effects in Alzheimer's disease that are large enough to be clinically detectable.

Methods

Overview analysis of published trials of ChEIs in which the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and a global clinical measure were primary outcomes. Two quantitative summary measures of the treatment effect (Cohen's d and the standardised response mean (SRM)) were calculated and presented as funnel plots. Observed cases analyses and intention to treat (ITT) with the last observation carried forward (LOCF) analyses were compared.

Results

The median Cohen's d effect sizes (ES) using ITT samples with LOCF for the ADAS-Cog were: low dose of a ChEI (n = 8 studies) median ES = 0.15, range = 0.03-0.22; medium dose (n = 13) median ES = 0.23, range = 0.12-0.29; high dose (n = 9) median ES = 0.28, range = 0.01-0.31. In general, the ES were larger when calculated as SRMs (for example, high dose ChEI studies, median SRM = 0.47; range = 0.30-0.63) and highest in the observed cases analyses (for example, high dose median SRM = 0.56, range = 0.35-0.78). Global clinical scales produced similar estimates of ES (for example, high dose ChEI, ITT/LOCF median Cohen's d = 0.29, range = 0.20-0.47).

Conclusions

ChEIs produce small-moderate effect sizes in clinical trials which are reproducible and demonstrate a dose response. Better descriptions of the patterns of treatment response are needed to guide individual patient decisions about the effectiveness of treatment, but group effects are evident and appear large enough to be clinically detectable.

SUBMITTER: Rockwood K

PROVIDER: S-EPMC1763555 | biostudies-literature | 2004 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Size of the treatment effect on cognition of cholinesterase inhibition in Alzheimer's disease.

Rockwood K K

Journal of neurology, neurosurgery, and psychiatry 20040501 5

<h4>Background</h4>Six cholinesterase inhibitors (ChEIs) have been tested in people with Alzheimer's disease, using methods currently required for regulatory approval. The clinical importance of their treatment effects is controversial.<h4>Objective</h4>To determine whether cholinesterase inhibition produces treatment effects in Alzheimer's disease that are large enough to be clinically detectable.<h4>Methods</h4>Overview analysis of published trials of ChEIs in which the Alzheimer's Disease Ass ...[more]

PMID: 15090558

Similar Datasets

Project description:BackgroundDelaying the transition from minimal cognitive impairment to Alzheimer's dementia is a major concern in Alzheimer's disease (AD) therapeutics. Pathological signs of AD occur years before the onset of clinical dementia. Thus, long-term therapeutic approaches, with safe, minimally invasive, and yet effective substances are recommended. There is a need to develop new drugs to delay Alzheimer's dementia. We have taken a nutritional supplement approach with genistein, a chemically defined polyphenol that acts by multimodal specific mechanisms. Our group previously showed that genistein supplementation is effective to treat the double transgenic (APP/PS1) AD animal model.MethodsIn this double-blind, placebo-controlled, bicentric clinical trial, we evaluated the effect of daily oral supplementation with 120 mg of genistein for 12 months on 24 prodromal Alzheimer's disease patients. The amyloid-beta deposition was analyzed using 18F-flutemetamol uptake. We used a battery of validated neurocognitive tests: Mini-Mental State Exam (MMSE), Memory Alteration Test (M@T), Clock Drawing Test, Complutense Verbal Learning Test (TAVEC), Barcelona Test-Revised (TBR), and Rey Complex Figure Test.ResultsWe report that genistein treatment results in a significant improvement in two of the tests used (dichotomized direct TAVEC, p = 0.031; dichotomized delayed Centil REY copy p = 0.002 and a tendency to improve in all the rest of them. The amyloid-beta deposition analysis showed that genistein-treated patients did not increase their uptake in the anterior cingulate gyrus after treatment (p = 0.878), while placebo-treated did increase it (p = 0.036). We did not observe significant changes in other brain areas studied.ConclusionsThis study shows that genistein may have a role in therapeutics to delay the onset of Alzheimer's dementia in patients with prodromal Alzheimer's disease. These encouraging results indicate that this should be followed up by a new study with more patients to further validate the conclusion that arises from this study.Trial registrationNCT01982578, registered on November 13, 2013.

Project description:ImportanceNew therapeutic approaches for Alzheimer disease (AD) are needed.ObjectiveTo assess whether idalopirdine, a selective 5-hydroxytryptamine-6 receptor antagonist, is effective for symptomatic treatment of mild to moderate AD.Design, setting, and participantsThree randomized clinical trials that included 2525 patients aged 50 years or older with mild to moderate AD (study 1: n = 933 patients at 119 sites; study 2: n = 858 at 158 sites; and study 3: n = 734 at 126 sites). The 24-week studies were conducted from October 2013 to January 2017; final follow-up on January 12, 2017.InterventionsIdalopirdine (10, 30, or 60 mg/d) or placebo added to cholinesterase inhibitor treatment (donepezil in studies 1 and 2; donepezil, rivastigmine, or galantamine in study 3).Main outcomes and measuresPrimary end point in all 3 studies: change in cognition total score (range, 0-70; a lower score indicates less impairment) from baseline to 24 weeks measured by the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog); key secondary end points: Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change Scale and 23-item Activities of Daily Living Inventory scores. Dose group efficacy required a significant benefit over placebo for the primary end point and 1 or more key secondary end points. Safety data and adverse event profiles were recorded.ResultsAmong 2525 patients randomized in the 3 trials (mean age, 74 years; mean baseline ADAS-Cog total score, 26; between 62% and 65% of participants were women), 2254 (89%) completed the studies. In study 1, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.37 for the 60-mg dose of idalopirdine group, 0.61 for the 30-mg dose group, and 0.41 for the placebo group (adjusted mean difference vs placebo, 0.05 [95% CI, -0.88 to 0.98] for the 60-mg dose group and 0.33 [95% CI, -0.59 to 1.26] for the 30-mg dose group). In study 2, the mean change in ADAS-Cog total score between baseline and 24 weeks was 1.01 for the 30-mg dose of idalopirdine group, 0.53 for the 10-mg dose group, and 0.56 for the placebo group (adjusted mean difference vs placebo, 0.63 [95% CI, -0.38 to 1.65] for the 30-mg dose group; given the gated testing strategy and the null findings at the 30-mg dose, statistical comparison of the 10-mg dose was not performed). In study 3, the mean change in ADAS-Cog total score between baseline and 24 weeks was 0.38 for the 60-mg dose of idalopirdine group and 0.82 for the placebo group (adjusted mean difference vs placebo, -0.55 [95% CI, -1.45 to 0.36]). Treatment-emergent adverse events occurred in between 55.4% and 69.7% of participants in the idalopirdine groups vs between 56.7% and 61.4% of participants in the placebo groups.Conclusions and relevanceIn patients with mild to moderate AD, the use of idalopirdine compared with placebo did not improve cognition over 24 weeks of treatment. These findings do not support the use of idalopirdine for the treatment of AD.Trial registrationclinicaltrials.gov Identifiers: NCT01955161, NCT02006641, and NCT02006654.

Dataset Information

Size of the treatment effect on cognition of cholinesterase inhibition in Alzheimer's disease.

Background

Objective

Methods

Results

Conclusions

Publications

Size of the treatment effect on cognition of cholinesterase inhibition in Alzheimer's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets