Supplementary materials: Evaluating amyloid-beta as a surrogate endpoint in trials of anti-amyloid-beta drugs in Alzheimer’s disease: a Bayesian meta-analysis

https://doi.org/10.6084/m9.figshare.30762215

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posted on 2025-12-02, 10:28 authored by Sa Ren, Janharpreet Singh, Sandro Gsteiger, Christopher Cogley, Ben Reed, Keith R Abrams, Dalia Dawoud, Rhiannon K Owen, Paul Tappenden, Terrence J Quinn, Sylwia BujkiewiczSylwia Bujkiewicz

These are peer-reviewed supplementary materials for the article 'Evaluating amyloid-beta as a surrogate endpoint in trials of anti-amyloid-beta drugs in Alzheimer’s disease: a Bayesian meta-analysis' published in the Journal of Comparative Effectiveness Research.Appendix A. Conversion of data on Aβ PET between Centiloid and SUVR scalesAppendix B. Literature review<ul><li>Table S1: Characteristics of included clinical trials</li></ul>Appendix C. Further Results<ul><li>Figure S1: Forest plot illustrating the observed treatment on Clinical Dementia Rating – Sum of Boxes (CDR-SOB) and the corresponding predicted effect on CDR-SOB using Daniels and Hughes model.</li><li>Figure S2: Bubble plot of the surrogate relationship between treatment effects on Aβ standardised uptake value ratio (SUVR) and Alzheimer’s Disease Assessment Scale--Cognitive Subscale (ADAS-Cog) with treatment effects on Aβ reported at earlier time points.</li><li>Figure S3: Bubble plot of the surrogate relationship between treatment effects on Aβ standardised uptake value ratio (SUVR) and Mini Mental State Examination (MMSE) with treatment effects on Aβ reported at earlier time points.</li><li>Figure S4: Bubble plot of the overall surrogate relationships with treatment effects on Aβ standardised uptake value ratio (SUVR) and Clinical Dementia Rating – Sum of Boxes (CDR-SOB) reported at the same time.</li><li>Figure S5: Bubble plot of the overall surrogate relationships with treatment effects on Aβ centiloids (with converted values) and Clinical Dementia Rating – Sum of Boxes (CDR-SOB) reported at the same time.</li><li>Figure S6: Bubble plot of the overall surrogate relationships with treatment effects on Aβ centiloids (without converted values) and Clinical Dementia Rating – Sum of Boxes (CDR-SOB) reported at the same time.</li><li>Figure S7: Forest plot of estimates of slope (red), intercept (green) and conditional variance (blue) for Aβ standardised uptake value ratio (SUVR) as a surrogate for Clinical Dementia Rating – Sum of Boxes (CDR-SOB).</li><li>Figure S8: Forest plot illustrating the observed treatment on Clinical Dementia Rating – Sum of Boxes (CDR-SOB) and the corresponding predicted effect on CDR-SOB using full exchangeability model.</li></ul>ReferencesAim: The use of amyloid-beta (Aβ) clearance to support regulatory approvals of drugs in Alzheimer’s disease (AD) remains controversial. We evaluate Aβ as a potential trial-level surrogate endpoint for clinical function in AD. Materials & methods: Data on the effectiveness of anti-Aβ monoclonal antibodies (MABs) on Aβ and multiple clinical outcomes were identified from randomized controlled trials through a literature review. A Bayesian bivariate meta-analysis was used to evaluate Aβ as a surrogate endpoint for clinical function across all MABs and for each individual anti-Aβ MAB. The analysis for individual therapies was conducted in subgroups of treatments and by applying Bayesian hierarchical models to borrow information across treatments. Results: We identified 23 randomized controlled trials with 39 treatment contrasts for seven MABs. The surrogate relationship between treatment effects on Aβ and Clinical Dementia Rating-Sum of Boxes (CDR-SOB) across all MABs was strong: with a meaningful slope of 1.41 (0.60, 2.21) and small variance of 0.02 (0.00, 0.05). For individual treatments, the surrogate relationships were suboptimal, displaying large uncertainty. Sharing information across treatments considerably reduced the uncertainty, resulting in moderate surrogate relationships for aducanumab and lecanemab. No meaningful association was detected for other clinical outcomes, including Mini Mental State Examination and Alzheimer’s Disease Assessment Scale-Cognitive Subscale. Conclusion: Although our results from the analysis of data across allMABs suggested that Aβ was a potential surrogate endpoint for CDR-SOB, individually the surrogacy patterns varied across treatments and showed no evidence of association. Bayesian information-sharing revealed moderate surrogate relationship only for aducanumab and lecanemab.