دورية أكاديمية
Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial.
| العنوان: | Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. |
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| المؤلفون: | Sims JR; Eli Lilly and Company, Indianapolis, Indiana., Zimmer JA; Eli Lilly and Company, Indianapolis, Indiana., Evans CD; Eli Lilly and Company, Indianapolis, Indiana., Lu M; Eli Lilly and Company, Indianapolis, Indiana., Ardayfio P; Eli Lilly and Company, Indianapolis, Indiana., Sparks J; Eli Lilly and Company, Indianapolis, Indiana., Wessels AM; Eli Lilly and Company, Indianapolis, Indiana., Shcherbinin S; Eli Lilly and Company, Indianapolis, Indiana., Wang H; Eli Lilly and Company, Indianapolis, Indiana., Monkul Nery ES; Eli Lilly and Company, Indianapolis, Indiana., Collins EC; Eli Lilly and Company, Indianapolis, Indiana., Solomon P; Boston Center for Memory and Boston University Alzheimer's Disease Center, Boston, Massachusetts., Salloway S; Department of Neurology and Department of Psychiatry, Alpert Medical School of Brown University, Providence, Rhode Island.; Butler Hospital, Providence, Rhode Island., Apostolova LG; Department of Neurology, Indiana University School of Medicine, Indianapolis., Hansson O; Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden; Memory Clinic, Skåne University Hospital, Lund, Sweden., Ritchie C; Scottish Brain Sciences, Edinburgh, United Kingdom., Brooks DA; Eli Lilly and Company, Indianapolis, Indiana., Mintun M; Eli Lilly and Company, Indianapolis, Indiana., Skovronsky DM; Eli Lilly and Company, Indianapolis, Indiana. |
| مؤلفون مشاركون: | TRAILBLAZER-ALZ 2 Investigators |
| المصدر: | JAMA [JAMA] 2023 Aug 08; Vol. 330 (6), pp. 512-527. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Medical Association Country of Publication: United States NLM ID: 7501160 Publication Model: Print Cited Medium: Internet ISSN: 1538-3598 (Electronic) Linking ISSN: 00987484 NLM ISO Abbreviation: JAMA Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Chicago : American Medical Association, 1960- |
| مواضيع طبية MeSH: | Alzheimer Disease*/diagnostic imaging , Alzheimer Disease*/drug therapy , Alzheimer Disease*/psychology , Cognitive Dysfunction*/etiology , Cognitive Dysfunction*/drug therapy, Humans ; Female ; Aged ; Male ; Double-Blind Method ; Treatment Outcome ; Brain ; Antibodies, Monoclonal/therapeutic use |
| مستخلص: | Importance: There are limited efficacious treatments for Alzheimer disease. Objective: To assess efficacy and adverse events of donanemab, an antibody designed to clear brain amyloid plaque. Design, Setting, and Participants: Multicenter (277 medical research centers/hospitals in 8 countries), randomized, double-blind, placebo-controlled, 18-month phase 3 trial that enrolled 1736 participants with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging from June 2020 to November 2021 (last patient visit for primary outcome in April 2023). Interventions: Participants were randomized in a 1:1 ratio to receive donanemab (n = 860) or placebo (n = 876) intravenously every 4 weeks for 72 weeks. Participants in the donanemab group were switched to receive placebo in a blinded manner if dose completion criteria were met. Main Outcomes and Measures: The primary outcome was change in integrated Alzheimer Disease Rating Scale (iADRS) score from baseline to 76 weeks (range, 0-144; lower scores indicate greater impairment). There were 24 gated outcomes (primary, secondary, and exploratory), including the secondary outcome of change in the sum of boxes of the Clinical Dementia Rating Scale (CDR-SB) score (range, 0-18; higher scores indicate greater impairment). Statistical testing allocated α of .04 to testing low/medium tau population outcomes, with the remainder (.01) for combined population outcomes. Results: Among 1736 randomized participants (mean age, 73.0 years; 996 [57.4%] women; 1182 [68.1%] with low/medium tau pathology and 552 [31.8%] with high tau pathology), 1320 (76%) completed the trial. Of the 24 gated outcomes, 23 were statistically significant. The least-squares mean (LSM) change in iADRS score at 76 weeks was -6.02 (95% CI, -7.01 to -5.03) in the donanemab group and -9.27 (95% CI, -10.23 to -8.31) in the placebo group (difference, 3.25 [95% CI, 1.88-4.62]; P < .001) in the low/medium tau population and -10.2 (95% CI, -11.22 to -9.16) with donanemab and -13.1 (95% CI, -14.10 to -12.13) with placebo (difference, 2.92 [95% CI, 1.51-4.33]; P < .001) in the combined population. LSM change in CDR-SB score at 76 weeks was 1.20 (95% CI, 1.00-1.41) with donanemab and 1.88 (95% CI, 1.68-2.08) with placebo (difference, -0.67 [95% CI, -0.95 to -0.40]; P < .001) in the low/medium tau population and 1.72 (95% CI, 1.53-1.91) with donanemab and 2.42 (95% CI, 2.24-2.60) with placebo (difference, -0.7 [95% CI, -0.95 to -0.45]; P < .001) in the combined population. Amyloid-related imaging abnormalities of edema or effusion occurred in 205 participants (24.0%; 52 symptomatic) in the donanemab group and 18 (2.1%; 0 symptomatic during study) in the placebo group and infusion-related reactions occurred in 74 participants (8.7%) with donanemab and 4 (0.5%) with placebo. Three deaths in the donanemab group and 1 in the placebo group were considered treatment related. Conclusions and Relevance: Among participants with early symptomatic Alzheimer disease and amyloid and tau pathology, donanemab significantly slowed clinical progression at 76 weeks in those with low/medium tau and in the combined low/medium and high tau pathology population. Trial Registration: ClinicalTrials.gov Identifier: NCT04437511. |
| التعليقات: | Comment in: JAMA. 2023 Jul 17;:. (PMID: 37459123) Comment in: JAMA. 2023 Aug 8;330(6):507-509. (PMID: 37459124) Comment in: JAMA. 2023 Aug 8;330(6):510-511. (PMID: 37459138) Comment in: Nat Rev Neurol. 2023 Oct;19(10):581-582. (PMID: 37658242) Comment in: JAMA. 2023 Dec 19;330(23):2304-2305. (PMID: 38112817) Comment in: JAMA. 2023 Dec 19;330(23):2304. (PMID: 38112820) |
| معلومات مُعتمدة: | S10 OD025214 United States OD NIH HHS |
| فهرسة مساهمة: | Investigator: R Abreu; P Agarwal; P Aggarwal; M Agronin; A Allen; D Altamirano; G Alva; J Andersen; A Anderson; D Anderson; J Arnold; T Asada; Y Aso; V Atit; R Ayala; M Badruddoja; H Badzio-Jagiello; M Bajacek; D Barton; D Bear; S Benjamin; R Bergeron; P Bhatia; S Black; A Block; M Bolouri; W Bond; J Bouthillier; S Brangman; B Brew; S Brisbin; T Brisken; A Brodtmann; M Brody; J Brosch; C Brown; P Brownstone; S Bukowczan; J Burns; A Cabrera; H Capote; A Carrasco; J Cevallos Yepez; E Chavez; H Chertkow; U Chyrchel-Paszkiewicz; A Ciabarra; E Clemmons; D Cohen; R Cohen; I Cohen; M Concha; B Costell; D Crimmins; Y Cruz-Pagan; A Cueli; R Cupelo; M Czarnecki; D Darby; PLJ Dautzenberg; P De Deyn; J De La Gandara; K Deck; D Dibenedetto; M Dibuono; E Dinnerstein; A Dirican; S Dixit; J Dobryniewski; R Drake; P Drysdale; R Duara; J Duffy; A Ellenbogen; V Faradji; M Feinberg; R Feldman; S Fishman; S Flitman; C Forchetti; I Fraga; A Frank; B Frishberg; H Fujigasaki; H Fukase; I Fumero; K Furihata; C Galloway; R Gandhi; K George; M Germain; D Gitelman; N Goetsch; D Goldfarb; M Goldstein; L Goldstick; Y Gonzalez Rojas; I Goodman; D Greeley; C Griffin; E Grigsby; D Grosz; K Hafner; D Hart; S Henein; B Herskowitz; S Higashi; Y Higashi; G Ho; J Hodgson; M Hohenberg; L Hollenbeck; R Holub; T Hori; J Hort; J Ilkowski; KJ Ingram; M Isaac; M Ishikawa; L Janu; M Johnston; W Julio; W Justiz; T Kaga; T Kakigi; M Kalafer; M Kamijo; J Kaplan; M Karathanos; S Katayama; S Kaul; A Keegan; D Kerwin; U Khan; A Khan; N Kimura; G Kirk; G Klodowska; H Kowa; C Kutz; J Kwentus; R Lai; A Lall; M Lawrence; E Lee; R Leon; G Linker; P Lisewski; J Liss; C Liu; S Losk; E Lukaszyk; J Lynch; S Macfarlane; J Macsweeney; N Mannering; O Markovic; D Marks; J Masdeu; Y Matsui; K Matsuishi; P Mcallister; B Mcconnehey; A Mcelveen; L Mcgill; A Mecca; M Mega; J Mensah; A Mickielewicz; A Minaeian; B Mocherla; C Murphy; P Murphy; H Nagashima; A Nair; M Nair; J Nardandrea; M Nash; Z Nasreddine; Y Nishida; J Norton; L Nunez; J Ochiai; T Ohkubo; Y Okamura; E Okorie; E Olivera; J O'mahony; O Omidvar; D Ortiz-Cruz; A Osowa; M Papka; A Parker; P Patel; A Patel; M Patel; C Patry; E Peckham; M Pfeffer; A Pietras; M Plopper; A Porsteinsson; R Poulin Robitaille; N Prins; O Puente; M Ratajczak; M Rhee; A Ritter; R Rodriguez; L Rodriguez Ables; J Rojas; J Ross; P Royer; J Rubin; D Russell; SM Rutgers; S Rutrick; M Sadowski; B Safirstein; T Sagisaka; D Scharre; L Schneider; C Schreiber; M Schrift; P Schulz; H Schwartz; J Schwartzbard; J Scott; L Selem; P Sethi; S Sha; K Sharlin; S Sharma; T Shiovitz; R Shiwach; M Sladek; B Sloan; A Smith; P Solomon; E Sorial; E Sosa; M Stedman; S Steen; L Stein; A Stolyar; J Stoukides; S Sudoh; J Sutton; J Syed; K Szigeti; H Tachibana; Y Takahashi; A Tateno; JD Taylor; K Taylor; O Tcheremissine; A Thebaud; S Thein; L Thurman; S Toenjes; H Toji; M Toma; D Tran; P Trueba; M Tsujimoto; R Turner; A Uchiyama; D Ussorowska; S Vaishnavi; E Valor; J Vandersluis; A Vasquez; J Velez; C Verghese; K Vodickova-Borzova; D Watson; D Weidman; D Weisman; A White; K Willingham; I Winkel; P Winner; J Winston; A Wolff; H Yagi; H Yamamoto; S Yathiraj; Y Yoshiyama; M Zboch |
| سلسلة جزيئية: | ClinicalTrials.gov NCT04437511 |
| المشرفين على المادة: | 0 (Antibodies, Monoclonal) |
| تواريخ الأحداث: | Date Created: 20230717 Date Completed: 20230809 Latest Revision: 20240326 |
| رمز التحديث: | 20240326 |
| مُعرف محوري في PubMed: | PMC10352931 |
| DOI: | 10.1001/jama.2023.13239 |
| PMID: | 37459141 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-3598 |
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| DOI: | 10.1001/jama.2023.13239 |