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000277740 037__ $$aDZNE-2025-00461
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000277740 1001_ $$aBateman, Randall J$$b0
000277740 245__ $$aSafety and efficacy of long-term gantenerumab treatment in dominantly inherited Alzheimer's disease: an open-label extension of the phase 2/3 multicentre, randomised, double-blind, placebo-controlled platform DIAN-TU trial.
000277740 260__ $$aLondon$$bLancet Publ. Group$$c2025
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000277740 520__ $$aAmyloid plaque removal by monoclonal antibody therapies slows clinical progression in symptomatic Alzheimer's disease; however, the potential for delaying the onset of clinical symptoms in asymptomatic people is unknown. The Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU) is an ongoing platform trial assessing the safety and efficacy of multiple investigational products in participants with dominantly inherited Alzheimer's disease (DIAD). Based on findings of amyloid removal and downstream biological effects from the gantenerumab group of the platform trial, we continued a 3-year open-label extension (OLE) study to assess the safety and efficacy of long-term treatment with high doses of gantenerumab.The randomised, placebo-controlled, double-blind, phase 2/3 multi-arm trial (DIAN-TU-001) assessed solanezumab or gantenerumab versus placebo in participants who were between 15 years before and 10 years after their estimated years to symptom onset and who had a Clinical Dementia Rating (CDR) global score of 0 (cognitively normal) to 1 (mild dementia). This study was followed by an OLE study of gantenerumab treatment, conducted at 18 study sites in Australia, Canada, France, Ireland, Puerto Rico, Spain, the UK, and the USA. For inclusion in the OLE, participants at risk for DIAD had participated in the double-blind period of DIAN-TU-001 and were required to know their mutation status. We investigated increasing doses of subcutaneous gantenerumab up to 1500 mg every 2 weeks. Due to the lack of a regulatory path for gantenerumab, the study was stopped early after a prespecified interim analysis (when most participants had completed 2 years of treatment) of the clinical measure CDR-Sum of Boxes (CDR-SB). The primary outcome for the final analysis was the amyloid plaque measure 11C-Pittsburgh compound-B positron emission tomography (PiB-PET) standardised uptake value ratio (SUVR [PiB-PET SUVR]) at 3 years, assessed in the modified intention-to-treat group (mITT; defined as participants who received any gantenerumab treatment post-OLE baseline, had at least one PiB-PET SUVR assessment before gantenerumab treatment, and a post-baseline assessment). All participants who received at least one dose of study drug in the OLE were included in the safety analysis. DIAN-TU-001 (NCT01760005) and the OLE (NCT06424236) are registered with ClinicalTrials.gov.Of 74 participants who were recruited into the OLE study between June 3, 2020, and April 22, 2021, 73 were enrolled and received gantenerumab treatment. 47 (64%) stopped dosing due to early termination of the study by the sponsor, and 13 (18%) prematurely discontinued the study for other reasons; 13 people completed 3 years of treatment. The mITT group for the primary analysis comprised 55 participants. At the interim analysis, the hazard ratio for clinical decline of CDR-SB in asymptomatic mutation carriers was 0·79 (n=53 [95% CI 0·47 to 1·32]) for participants who were treated with gantenerumab in either the double-blind or OLE period (Any Gant), and 0·53 (n=22 [0·27 to 1·03]) for participants who were treated with gantenerumab the longest (Longest Gant). At the final analysis, the adjusted mean change from OLE baseline to year 3 in PiB-PET SUVR was -0·71 SUVR (95% CI -0·88 to -0·53, p<0·0001). Amyloid-related imaging abnormalities occurred in 53% (39 of 73) of participants: 47% (34 of 73) with microhaemorrhages, 30% (22 of 73) with oedema, and 6% (five of 73) were associated with superficial siderosis. No treatment-associated macrohaemorrhages or deaths occurred.Partial or short-term amyloid removal did not show significant clinical effects. However, long-term full amyloid removal potentially delayed symptom onset and dementia progression. Our conclusions are limited due to the OLE design and use of external controls and need to be confirmed in long-term trials.National Institute on Aging, Alzheimer's Association, GHR Foundation, and F Hoffmann-La Roche/Genentech.
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000277740 650_7 $$2NLM Chemicals$$aAntibodies, Monoclonal, Humanized
000277740 650_7 $$04DF060P933$$2NLM Chemicals$$agantenerumab
000277740 650_7 $$05D6PWO0333$$2NLM Chemicals$$asolanezumab
000277740 650_2 $$2MeSH$$aHumans
000277740 650_2 $$2MeSH$$aAntibodies, Monoclonal, Humanized: therapeutic use
000277740 650_2 $$2MeSH$$aAntibodies, Monoclonal, Humanized: pharmacology
000277740 650_2 $$2MeSH$$aAntibodies, Monoclonal, Humanized: administration & dosage
000277740 650_2 $$2MeSH$$aDouble-Blind Method
000277740 650_2 $$2MeSH$$aMale
000277740 650_2 $$2MeSH$$aFemale
000277740 650_2 $$2MeSH$$aAlzheimer Disease: drug therapy
000277740 650_2 $$2MeSH$$aAlzheimer Disease: genetics
000277740 650_2 $$2MeSH$$aMiddle Aged
000277740 650_2 $$2MeSH$$aTreatment Outcome
000277740 650_2 $$2MeSH$$aAdult
000277740 650_2 $$2MeSH$$aAged
000277740 7001_ $$aLi, Yan$$b1
000277740 7001_ $$aMcDade, Eric M$$b2
000277740 7001_ $$aLlibre-Guerra, Jorge J$$b3
000277740 7001_ $$aClifford, David B$$b4
000277740 7001_ $$aAtri, Alireza$$b5
000277740 7001_ $$aMills, Susan L$$b6
000277740 7001_ $$aSantacruz, Anna M$$b7
000277740 7001_ $$aWang, Guoqiao$$b8
000277740 7001_ $$aSupnet, Charlene$$b9
000277740 7001_ $$aBenzinger, Tammie L S$$b10
000277740 7001_ $$aGordon, Brian A$$b11
000277740 7001_ $$aIbanez, Laura$$b12
000277740 7001_ $$aKlein, Gregory$$b13
000277740 7001_ $$aBaudler, Monika$$b14
000277740 7001_ $$aDoody, Rachelle S$$b15
000277740 7001_ $$aDelmar, Paul$$b16
000277740 7001_ $$aKerchner, Geoffrey A$$b17
000277740 7001_ $$aBittner, Tobias$$b18
000277740 7001_ $$aWojtowicz, Jakub$$b19
000277740 7001_ $$aBonni, Azad$$b20
000277740 7001_ $$aFontoura, Paulo$$b21
000277740 7001_ $$aHofmann, Carsten$$b22
000277740 7001_ $$aKulic, Luka$$b23
000277740 7001_ $$aHassenstab, Jason$$b24
000277740 7001_ $$aAschenbrenner, Andrew J$$b25
000277740 7001_ $$aPerrin, Richard J$$b26
000277740 7001_ $$aCruchaga, Carlos$$b27
000277740 7001_ $$aRenton, Alan E$$b28
000277740 7001_ $$aXiong, Chengjie$$b29
000277740 7001_ $$aGoate, Alison A$$b30
000277740 7001_ $$aMorris, John C$$b31
000277740 7001_ $$aHoltzman, David M$$b32
000277740 7001_ $$aSnider, B Joy$$b33
000277740 7001_ $$aMummery, Catherine$$b34
000277740 7001_ $$aBrooks, William S$$b35
000277740 7001_ $$aWallon, David$$b36
000277740 7001_ $$aBerman, Sarah B$$b37
000277740 7001_ $$aRoberson, Erik$$b38
000277740 7001_ $$aMasters, Colin L$$b39
000277740 7001_ $$aGalasko, Douglas R$$b40
000277740 7001_ $$aJayadev, Suman$$b41
000277740 7001_ $$aSanchez-Valle, Rachel$$b42
000277740 7001_ $$aPariente, Jeremie$$b43
000277740 7001_ $$aKinsella, Justin$$b44
000277740 7001_ $$avan Dyck, Christopher H$$b45
000277740 7001_ $$aGauthier, Serge$$b46
000277740 7001_ $$aHsiung, Ging-Yuek Robin$$b47
000277740 7001_ $$aMasellis, Mario$$b48
000277740 7001_ $$aDubois, Bruno$$b49
000277740 7001_ $$aHonig, Lawrence S$$b50
000277740 7001_ $$aJack, Clifford R$$b51
000277740 7001_ $$aDaniels, Alisha$$b52
000277740 7001_ $$aAguillón, David$$b53
000277740 7001_ $$aAllegri, Ricardo$$b54
000277740 7001_ $$aChhatwal, Jasmeer$$b55
000277740 7001_ $$aDay, Gregory$$b56
000277740 7001_ $$aFox, Nick C$$b57
000277740 7001_ $$aHuey, Edward$$b58
000277740 7001_ $$aIkeuchi, Takeshi$$b59
000277740 7001_ $$0P:(DE-2719)2000010$$aJucker, Mathias$$b60$$udzne
000277740 7001_ $$0P:(DE-HGF)0$$aLee, Jae-Hong$$b61
000277740 7001_ $$aLevey, Allan I$$b62
000277740 7001_ $$0P:(DE-2719)2811659$$aLevin, Johannes$$b63$$udzne
000277740 7001_ $$aLopera, Francisco$$b64
000277740 7001_ $$aRoh, JeeHoon$$b65
000277740 7001_ $$aRosa-Neto, Pedro$$b66
000277740 7001_ $$aSchofield, Peter R$$b67
000277740 7001_ $$aUnit, Dominantly Inherited Alzheimer's Disease-Trials$$b68$$eCollaboration Author
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