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Application of Meta-analysis to Evaluate Relationships Among ARIA-E Rate, Amyloid Reduction Rate, and Clinical Cognitive Response in Amyloid Therapeutic Clinical Trials for Early Alzheimer's Disease
Wang D, Kowalewski EK, Koch G.. Therapeutic innovation & regulatory science, 2022-03-23
Topic: Drug trials: efficacy and safety
Background Removal of the extracellular Aβ plaques in the brain is one of the mechanisms to treat Alzheimer's disease (AD). Separate clinical trials for several therapeutic compounds that target amyloid plaque reduction have shown noteworthy correlations among plaque removal, the Amyloid-Related Imaging Abnormalities (ARIA) rate, and clinical efficacy of the treatment. The relationships among therapeutic dose levels, the rate of amyloid removal, and the clinical efficacy deserve further investigation across therapeutic agents, particularly for clinical trials to provide insights for strategies to develop amyloid therapies in Alzheimer's disease. Methods Published data summaries from clinical trials with amyloid therapies of aducanumab, donanemab, lecanemab, and gantenerumab are evaluated with meta-analyses. Linear mixed models for repeated measurements for visits and random study effects are applied to analyze amyloid centiloid value reduction from baseline and clinical cognition change from baseline for treatment groups according to doses and compounds for the clinical trials. Logistic regression analysis is applied to evaluate the relationship between the amyloid removal rate and the ARIA-Edema (ARIA-E) rate across different dose groups and clinical trials. Results The extent of amyloid removal varies among therapeutic agents and their dose levels. Across treatment groups and clinical trials, amyloid centiloid value reductions at Weeks 26 and 52 are strongly correlated with both ARIA-E rate over 78 weeks and the clinical efficacy response in the Clinical Dementia-Rating Scale Sum of Boxes (CDR-SB) score change from baseline at Week 78; and the Spearman rank correlations for amyloid reduction at Week 52 are stronger as - 0.79 with the ARIA-E rate over 78 weeks and 0.73 with the Week 78 CDR-SB score change from baseline. Conclusion Aβ plaques removal in the brain due to amyloid therapy is strongly correlated with a better clinical response in patients with early Alzheimer's disease and a higher ARIA-E rate for the treatment groups and clinical trials in this meta-analysis. These relationships suggest that the balance between the clinical efficacy response and safety in ARIA-E rate is relevant for the choice of doses for amyloid therapies in confirmatory clinical trials.
Key findings
- Results The extent of amyloid removal varies among therapeutic agents and their dose levels.
- These relationships suggest that the balance between the clinical efficacy response and safety in ARIA-E rate is relevant for the choice of doses for amyloid therapies in confirmatory clinical trials.
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Study details
- Study designmeta-analysis
- Evidence strengthHigh
How this study scored 67/100
Published in a peer-reviewed journal, and it is a meta-analysis pooling many studies. Scored zero for sample size, effect reported and studied in people because the record does not state it. We have no data on journal's citation record, 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 multi-centre collaboration, so those were left out: it earned 39 of the 58 points we could judge it on, which is 67 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Therapeutic innovation & regulatory science) |
| Journal's citation record | — / 4 | No journal record from OpenAlex — left out of this score |
| Study design | 12 / 12 | A meta-analysis pooling many studies |
| Strength of evidence | 5 / 5 | Rated “high” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 3 / 5 | 2022 — within 6 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) |
| Randomised / blinded | 0 / 2 | A review of other studies — randomisation is not credited here |
| 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 |
| Multi-centre collaboration | — / 3 | Institutions not listed — left out of this score |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 35320578) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 39 / 58 | Scored on 11 of 20 parts. We have no data for the rest, so they are left out: 39 of the 58 points we could judge it on is 67 out of 100. |
| Total | 67 / 100 | — |
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APA 7th
Wang, D., Kowalewski, E. K., & Koch, G. (2022). Application of Meta-analysis to Evaluate Relationships Among ARIA-E Rate, Amyloid Reduction Rate, and Clinical Cognitive Response in Amyloid Therapeutic Clinical Trials for Early Alzheimer's Disease. Therapeutic innovation & regulatory science. https://doi.org/10.1007/s43441-022-00390-4
Vancouver
Wang D, Kowalewski EK, Koch G. Application of Meta-analysis to Evaluate Relationships Among ARIA-E Rate, Amyloid Reduction Rate, and Clinical Cognitive Response in Amyloid Therapeutic Clinical Trials for Early Alzheimer's Disease. Therapeutic innovation & regulatory science. 2022. doi:10.1007/s43441-022-00390-4. PMID: 35320578.
BibTeX
@article{wang2022-35320578,
author = {Wang, D. and Kowalewski, E. K. and Koch, G.},
title = {{Application of Meta-analysis to Evaluate Relationships Among ARIA-E Rate, Amyloid Reduction Rate, and Clinical Cognitive Response in Amyloid Therapeutic Clinical Trials for Early Alzheimer's Disease}},
journal = {Therapeutic innovation \& regulatory science},
year = {2022},
doi = {10.1007/s43441-022-00390-4},
pmid = {35320578},
url = {https://doi.org/10.1007/s43441-022-00390-4}
}