{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:33:04Z","timestamp":1787725984936,"version":"build-2784847793"},"reference-count":32,"publisher":"SAGE Publications","issue":"1","license":[{"start":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T00:00:00Z","timestamp":1757894400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"Advantage Therapeutics Inc."}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The AFF006 trial (NCT01117818) provided unexpected evidence of benefits of the vaccine adjuvant AD04 (aluminum oxyhydroxide) in patients with early Alzheimer's disease (AD), compared with AD02, a vaccine consisting of a peptide that mimics the N-terminal region of human amyloid-\u03b2 (A\u03b2) conjugated with keyhole limpet hemocyanin.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>The objective of this post hoc analysis was to assess whether this unexpected benefit of AD04 was an artifact of multiple testing (i.e., type I error inflation) or a robust result.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this post hoc assessment, we used permutation testing to estimate type I error inflation due to the evaluation of multiple outcomes in AFF006. Efficacy was assessed using a patient-level global statistical test combining composite endpoints of cognition, function, and global AD. In addition, we examined the observed treatment benefits of AD04 in the context of effects observed in trials of aducanumab, donanemab, and lecanemab, monoclonal anti-A\u03b2 antibodies that received regulatory approval for AD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The global statistical test suggested a treatment benefit of AD04 versus ineffective AD02 arms, even after accounting for multiplicity (primary methodology p-value, 0.03; permutation test p-value, 0.02). The observed effect estimates for AD04 compared favorably with approved monoclonal antibodies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Post-hoc analyses are hypothesis generating rather than confirmatory. Adjusting for multiplicity using permutation testing can determine whether post-hoc effects are worth pursuing, or unlikely to be confirmed. These analyses have motivated a follow-up prospective randomized controlled trial, ADVANCE (EudraCT 2022-003532-73), in which optimized AD04 dosing will be compared to placebo in early AD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/13872877251375985","type":"journal-article","created":{"date-parts":[[2025,9,15]],"date-time":"2025-09-15T17:49:50Z","timestamp":1757958590000},"page":"234-242","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":4,"title":["Efficacy of AD04, an aluminum-based vaccine adjuvant, in patients with early Alzheimer's disease: Post hoc analysis of AFF006 (NCT01117818), a proof-of-concept, phase 2 randomized controlled trial"],"prefix":"10.1177","volume":"108","author":[{"given":"Benjamin","family":"Haaland","sequence":"first","affiliation":[{"name":"Pentara Corporation, Millcreek, UT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel P","family":"Dickson","sequence":"additional","affiliation":[{"name":"Pentara Corporation, Millcreek, UT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agustin Fern\u00e1ndez","family":"Santana","sequence":"additional","affiliation":[{"name":"Advantage Therapeutics, Miami, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolph E","family":"Tanzi","sequence":"additional","affiliation":[{"name":"Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Dubois","sequence":"additional","affiliation":[{"name":"Alzheimer Research Center IM2A, GH Piti\u00e9-Salp\u00eatri\u00e8re, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oliver","family":"Peters","sequence":"additional","affiliation":[{"name":"Department of Psychiatry and Neurosciences, CBF, Charit\u00e9, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"Grimmer","sequence":"additional","affiliation":[{"name":"School of Medicine and Health, Klinikum rechts der Isar, Centre for Cognitive Disorders, Department of Psychiatry and Psychotherapy, Technical University of Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-5986-7758","authenticated-orcid":false,"given":"Joshua","family":"Christensen","sequence":"additional","affiliation":[{"name":"Pentara Corporation, Millcreek, UT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Mallinckrodt","sequence":"additional","affiliation":[{"name":"Pentara Corporation, Millcreek, UT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9410-124X","authenticated-orcid":false,"given":"Achim","family":"Schneeberger","sequence":"additional","affiliation":[{"name":"Advantage Therapeutics, Miami, FL, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne B","family":"Hendrix","sequence":"additional","affiliation":[{"name":"Pentara Corporation, Millcreek, UT, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2025,9,15]]},"reference":[{"key":"e_1_3_3_2_2","first-page":"91","article-title":"Methodological aspects of the phase II study AFF006 evaluating amyloid-beta -targeting vaccine AFFITOPE(R) AD02 in early Alzheimer's disease - prospective use of novel composite scales","volume":"2","author":"Hendrix S","year":"2015","unstructured":"Hendrix S, Ellison N, Stanworth S, et al. 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