{"doi":"10.14283/jpad.2022.30","title":"Two Randomized Phase 3 Studies of Aducanumab in Early Alzheimer's Disease","abstract":"BACKGROUND: Alzheimer's disease is a progressive, irreversible, and fatal disease for which accumulation of amyloid beta is thought to play a key role in pathogenesis. Aducanumab is a human monoclonal antibody directed against aggregated soluble and insoluble forms of amyloid beta. OBJECTIVES: We evaluated the efficacy and safety of aducanumab in early Alzheimer's disease. DESIGN: EMERGE and ENGAGE were two randomized, double-blind, placebo-controlled, global, phase 3 studies of aducanumab in patients with early Alzheimer's disease. SETTING: These studies involved 348 sites in 20 countries. PARTICIPANTS: Participants included 1638 (EMERGE) and 1647 (ENGAGE) patients (aged 50-85 years, confirmed amyloid pathology) who met clinical criteria for mild cognitive impairment due to Alzheimer's disease or mild Alzheimer's disease dementia, of which 1812 (55.2%) completed the study. INTERVENTION: Participants were randomly assigned 1:1:1 to receive aducanumab low dose (3 or 6 mg/kg target dose), high dose (10 mg/kg target dose), or placebo via IV infusion once every 4 weeks over 76 weeks. MEASUREMENTS: The primary outcome measure was change from baseline to week 78 on the Clinical Dementia Rating Sum of Boxes (CDR-SB), an integrated scale that assesses both function and cognition. Other measures included safety assessments; secondary and tertiary clinical outcomes that assessed cognition, function, and behavior; and biomarker endpoints. RESULTS: EMERGE and ENGAGE were halted based on futility analysis of data pooled from the first approximately 50% of enrolled patients; subsequent efficacy analyses included data from a larger data set collected up to futility declaration and followed prespecified statistical analyses. The primary endpoint was met in EMERGE (difference of -0.39 for high-dose aducanumab vs placebo [95% CI, -0.69 to -0.09; P=.012; 22% decrease]) but not in ENGAGE (difference of 0.03, [95% CI, -0.26 to 0.33; P=.833; 2% increase]). Results of biomarker substudies confirmed target engagement and dose-dependent reduction in markers of Alzheimer's disease pathophysiology. The most common adverse event was amyloid-related imaging abnormalities-edema. CONCLUSIONS: Data from EMERGE demonstrated a statistically significant change across all four primary and secondary clinical endpoints. ENGAGE did not meet its primary or secondary endpoints. A dose- and time-dependent reduction in pathophysiological markers of Alzheimer's disease was observed in both trials.","journal":"The Journal of Prevention of Alzheimer s Disease","year":2022,"id":231562,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1336,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9543,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":229340,"name":"Paul Aisen","orcid":null,"position":1,"is_corresponding":false},{"id":242544,"name":"Frederik Barkhof","orcid":"0000-0003-3543-3706","position":2,"is_corresponding":false},{"id":838767,"name":"Spyros Chalkias","orcid":"0000-0002-6254-1158","position":3,"is_corresponding":false},{"id":523807,"name":"Tianle Chen","orcid":"0009-0000-5930-0145","position":4,"is_corresponding":false},{"id":838768,"name":"Sarah Cohen","orcid":"0000-0003-1188-1854","position":5,"is_corresponding":false},{"id":840344,"name":"Gersham Dent","orcid":null,"position":6,"is_corresponding":false},{"id":65584,"name":"Oskar Hansson","orcid":"0000-0001-8467-7286","position":7,"is_corresponding":false},{"id":838769,"name":"Katie Harrison","orcid":"0000-0001-5534-1417","position":8,"is_corresponding":false},{"id":840345,"name":"Christian von Hehn","orcid":null,"position":9,"is_corresponding":false},{"id":55002,"name":"Takeshi Iwatsubo","orcid":"0000-0003-1160-8129","position":10,"is_corresponding":false},{"id":840346,"name":"Craig Mallinckrodt","orcid":null,"position":11,"is_corresponding":false},{"id":840347,"name":"Cath Mummery","orcid":null,"position":12,"is_corresponding":false},{"id":838770,"name":"Kumar Kandadi Muralidharan","orcid":"0000-0002-7879-5769","position":13,"is_corresponding":false},{"id":838771,"name":"Ivan Nestorov","orcid":"0000-0002-1834-2792","position":14,"is_corresponding":false},{"id":840348,"name":"Laura Nisenbaum","orcid":null,"position":15,"is_corresponding":false},{"id":840349,"name":"Raj Rajagovindan","orcid":null,"position":16,"is_corresponding":false},{"id":840350,"name":"LeAnne Skordos","orcid":null,"position":17,"is_corresponding":false},{"id":26966,"name":"Y. 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