Lead Investigator: Iris Sommer, University Medical Center Groningen
Title of Proposal Research: Meta-analysis of efficacy of cholinesterase inhibitors on individual neuropsychiatric symptoms in Alzheimer’s disease, Parkinson’s disease and dementia with Lewy bodies
Vivli Data Request: 5924
Funding Source: Government Funding (ZonMw project number 636310010)
Potential Conflicts of Interest: None
Summary of the Proposed Research:
Alzheimer’s disease (AD) is the most prevalent type of dementia, affecting approximately 24 million people globally. It is estimated that Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) together affect an additional 10 million people globally (~1.5% of the elderly population).
Cognitive deficits, such as problems with memory, planning and reasoning, and neuropscyhiatric disturbances, such as depression and anxiety, are both important features of these diseases.
Cholinesterase inhibitors (ChEIs), such as donepezil and rivastigmine, form a type of drug that has a well established effect on the cognitive deficits. However, the beneficial effect on neuropsychiatric disturbances is much less clear. A possible explanation for the inconsistent results of ChEIs on neuropsychiatric disturbances is that the definition of ‘neuropsychiatric’ is too broad, as it includes symptoms such as hallucinations and delusions, but also depression, anxiety and irritability, among others.
Therefore, we want to conduct a meta-analysis on the efficacy of ChEIs on all individual items of neuropsychiatric outcome measures, to assess which subdomains benefit from treatment and which do not. Individual trials are usually not powered for this subanalysis, which is why we want to pool all the available data.
We believe that this meta-analysis will form the basis for a more targeted approach for treating neuropsychiatric symptoms in PD, AD and DLB.
Statistical Analysis Plan:
The criteria used for selecting a study were: randomized, double-blind, placebo-controlled trials assessing efficacy of rivastigmine, donepezil or galantamine in AD, PD or DLB with a neuropsychiatric outcome measure.
Effect sizes are computed using Comprehensive Meta-Analysis Version (CMA) 2.0, Biostat, or R if it is not achieved to run CMA on the research environment. For every individual study, Hedges’ g will be calculated for each neuropsychiatric subdomain. To obtain this effect size, the mean difference between change scores (end of treatment minus baseline and SD) of the active treatment group vs. placebo group is used for each individual neuropsychiatric subdomain, or pre- and post-means (+ SDs) per treatment arm. To avoid overestimation of the true effect sizes caused by the pre-post treatment correlation, change scores are preferred. When these values are not reported, we use exact F-, t-, or p-values. All effect sizes are calculated twice independently from the original articles to check for errors. Studies will be combined to calculate a mean weighted ES (Hedges’ g) for the effect on individual neuropsychiatric subdomains, using a random effects model. Studies with multiple treatment groups (e.g. different treatment doses) and one placebo group were entered as individual study samples. ES of p<0.05 (two-tailed) will be considered statistically significant, 0.2 reflecting a small, 0.5 a medium, and ⩾0.8 a large effect.
To investigate whether studies can be combined to share a common population effect size, the Q-value and I2–statistic will be evaluated for each analysis. The Q-statistic tests the existence of heterogeneity and displays a chi-square distribution with k − 1 degrees of freedom (k = number of study samples). Q-values higher than the degrees of freedom (df) indicate significant between-studies variability. I2 indicates the proportion of the observed variance in true effect sizes rather than sampling error, ranging from 0 to 100%. I2-values of 25, 50, and 75% will be considered as low, moderate, and high heterogeneity, respectively. For significant results, potential publication bias will be investigated by means of a visual inspection of the funnel plot and Egger’s test (p<0.1, two-tailed).
Further investigating potential heterogeneity between studies, moderator analyses will be performed to evaluate whether study characteristics covary with intervention effectiveness; including baseline NPI and baseline MMSE, time since diagnosis (years), treatment duration (weeks) and age (years) and gender distribution (% male) of the included study samples. Additionally, subgroup analysis will be performed to evaluate whether the effect on favorable outcome differs between the different types of ChEIs (rivastigmine, donepezil and galantamine) or the different diagnoses (Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies). P-values < 0.05 will be considered significant.
Requested Studies:
A 24-week, Double-blind, Double-dummy, Randomized, Parallel-group Study to Investigate the Effects of Rosiglitazone (Extended Release Tablets), Donepezil, and Placebo as Monotherapy on Cognition and Overall Clinical Response in APOE ε4-stratified Subjects With Mild to Moderate Alzheimer’s Disease. (REFLECT-1)
Sponsor: GlaxoSmithKline
Study ID: NCT00428090
Sponsor ID: 105640
Efficacy and Safety Study for Subjects With Mild-to-Moderate Alzheimer’s Disease
Data Contributor: AbbVie
Sponsor ID: M10-984
Evaluate the Efficacy and Safety of ABT-126 in Subjects With Mild to Moderate Alzheimer’s Disease
Data Contributor: AbbVie
Sponsor ID: M10-985
Efficacy and Safety Study of ABT-288 in Subjects With Mild-to-Moderate Alzheimer’s Disease
Data Contributor: AbbVie
Sponsor ID: M10-822
Galantamine in the Treatment of Alzheimer’s Disease: Flexible Dose Range Trial
Sponsor: Johnson & Johnson
Study ID: NCT00253227
Sponsor ID: CR006028
Placebo-Controlled Evaluation of Galantamine in the Treatment of Alzheimer’s Disease: Safety and Efficacy of a Controlled-Release Formulation
Sponsor: Johnson & Johnson
Study ID: NCT00253214
Sponsor ID: CR006037
Placebo-controlled evaluation of galantamine in the treatment of Alzheimer’s disease: Evaluation of safety and efficacy under a slow titration regimen
Sponsor: Johnson & Johnson
Study ID: GAL-USA-10
Sponsor ID: GAL-USA-10
Public Disclosures:
d’Angremont E, Begemann MJH, van Laar T, Sommer IEC. Cholinesterase Inhibitors for Treatment of Psychotic Symptoms in Alzheimer Disease and Parkinson Disease: A Meta-analysis. JAMA Neurol. Published online June 26, 2023. doi:10.1001/jamaneurol.2023.1835