P4‐404: Donepezil therapy for patients with Alzheimer's disease: Treatment benefits in “nonresponders”
Bibliographic record
Abstract
There has been an expectation for some that treatment benefit in Alzheimer's disease (AD) is demonstrated only by improvement or stabilization. Thus, patients demonstrating less-than-expected decline may be erroneously characterized as “nonresponders”. The objective of these analyses was to investigate whether donepezil-treated patients classified as “nonresponders” actually experience less-than-expected decline compared with matched placebo patients. Data were pooled from 4 randomized, double-blind, placebo-controlled studies of donepezil for AD. Analyses were restricted to 1439 patients with baseline Mini-Mental State Examination (MMSE) scores ≥10 (range, 10–28). Changes from baseline to Week 24 on the MMSE and Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) were assessed in placebo and donepezil-treated patients meeting criteria for 3 definitions of “nonresponse” at Week 24, as follows: (1) decline in cognition (MMSE) only; (2) decline in cognition (MMSE) and global; (3) decline in cognition (MMSE), global and function. A lower percentage of donepezil-treated patients than placebo patients met the criteria for each definition of “nonresponse”: (1) 31% versus 45%; (2) 14% versus 28%; (3) 6% versus 14%. Importantly, although placebo percentages were smaller using more stringent definitions of “nonresponse” (definitions 2 and 3), more than twice as many placebo patients met the definition criteria compared with donepezil-treated patients. Regardless of the definition, the odds of declining were significantly reduced for donepezil-treated patients versus placebo patients (P<0.0001; all definitions). Among patients meeting criteria for definitions 1 and 2, mean declines in MMSE and ADAS-cog scores from baseline to Week 24 were significantly greater for placebo than donepezil-treated patients (P<0.03 for both definitions); among patients meeting criteria for the most stringent definition of “nonresponse”, definition 3, mean declines in MMSE and ADAS-cog from baseline were also greater for placebo patients, but between-group differences were not statistically significant. In this population of mild to moderate AD patients, donepezil treatment was associated with reduced worsening of clinical AD symptoms during the 6-month study period. These analyses demonstrate that AD patients characterized as “nonresponders” to donepezil therapy may still derive benefits over placebo/untreated patients. This is an important finding and concept in assessing treatment benefits in a progressive disease.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.005 | 0.004 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.002 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".