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Reducing placebo response in clinical trials of agitation in Alzheimer’s disease
Knudson KC, Anderson KM, Ballard M, Lenz RA, Dam T, Sagman D, Brandon NJ, Banerjee T et al.. medRxiv, 2026-06-04
Topic: Drug trials: efficacy and safety
Plain-language summary
High placebo response is an obstacle in developing drugs to treat agitation in Alzheimer’s disease (AAD), a prevalent and burdensome symptom. However, it has proved challenging to develop actionable models of placebo response that 1) can be applied prospectively, requiring only information available at screening or baseline, 2) yield strategies for reducing placebo response without equally depressing drug response, and 3) show generalizability across trials. Here, we first investigated placebo response in AAD at the trial level using meta-regression applied to 23 clinical trials. Meta-regression identified several factors associated with increased placebo response, but most of these factors were non-specific such that they predicted improvements in drug response as well. We therefore turned to individual level clinical trial datasets and applied causal modeling to predict which participants would have high placebo response relative to predicted drug response. We successfully built and validated the causal model across two independent clinical trials of risperidone and haloperidol at the level of individual patients (ability to predict subsequent improvement on drug or placebo). Crucially, we also found efficacy improvements in the overall trial through in silico exclusion/screen failing of high placebo-predicted subjects. We further characterized features most associated with placebo response to improve explainability and, lastly, validated the effect of these features at the trial level in clinical trials of galantamine, an acetylcholinesterase inhibitor (hence in a different class of drugs than those in the other two trials used). Taken together, we have developed and applied a causal modeling framework for reducing placebo response and increasing trial-level efficacy in neuropsychiatry clinical trials using historical trial datasets.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Knudson, K. C., Anderson, K. M., Ballard, M., Lenz, R. A., Dam, T., Sagman, D., et al. (2026). Reducing placebo response in clinical trials of agitation in Alzheimer’s disease. medRxiv. https://doi.org/10.64898/2026.06.03.26354808
Vancouver
Knudson KC, Anderson KM, Ballard M, Lenz RA, Dam T, Sagman D, et al. Reducing placebo response in clinical trials of agitation in Alzheimer’s disease. medRxiv. 2026. doi:10.64898/2026.06.03.26354808.
BibTeX
@article{knudson2026-59dea31b,
author = {Knudson, K. C. and Anderson, K. M. and Ballard, M. and Lenz, R. A. and Dam, T. and Sagman, D. and Brandon, N. J. and Banerjee, T. and others},
title = {{Reducing placebo response in clinical trials of agitation in Alzheimer’s disease}},
journal = {medRxiv},
year = {2026},
doi = {10.64898/2026.06.03.26354808},
url = {https://doi.org/10.64898/2026.06.03.26354808}
}
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Key findings
- Meta-regression identified several factors associated with increased placebo response, but most of these factors were non-specific such that they predicted improvements in drug response as well.
- Crucially, we also found efficacy improvements in the overall trial through in silico exclusion/screen failing of high placebo-predicted subjects.
- We further characterized features most associated with placebo response to improve explainability and, lastly, validated the effect of these features at the trial level in clinical trials of galantamine, an acetylcholinesterase inhibitor (hence in a different class of drugs than those in the other two trials used).
- Taken together, we have developed and applied a causal modeling framework for reducing placebo response and increasing trial-level efficacy in neuropsychiatry clinical trials using historical trial datasets.
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Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 21 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it. We have no data on times cited, citations per year, impact for its field and year, cited by studies here, still being cited, senior author's track record, institution's track record and multicenter collaboration, so those were left out: it earned 13 of the 62 points we could judge it on, which is 21 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | — / 7 | No citation count (not found in OpenAlex) — left out of this score |
| Citations per year | — / 5 | No citation count or no year — left out of this score |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | — / 6 | Not yet checked against this library's citation graph — left out of this score |
| Still being cited | — / 4 | No yearly citation counts — left out of this score |
| Senior author's track record | — / 4 | Senior author's record not available — left out of this score |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multicenter collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 13 / 62 | Scored on 12 of 20 parts. We have no data for the rest, so they are left out: 13 of the 62 points we could judge it on is 21 out of 100. |
| Total | 21 / 100 | Capped to 16 because this is not a peer-reviewed article. |
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