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Nilvadipine in mild to moderate alzheimer disease: a randomised controlled trial

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Show simple item record Lawlor, Brian Segurado, Ricardo Kennelly, Sean Olde Rikkert, Marcel G. M. Howard, Robert Pasquier, Florence Borjesson-Hanson, Anne Tsolaki, Magda Lucca, Ugo William Molloy, D Coen, Robert Riepe, Matthias W. Kálmán, János Kenny, Rose Anne Cregg, Fiona O'Dwyer, Sarah Walsh, Cathal Dominic Adams, Jessica Banzi, Rita Breuilh, Laetitia Daly, Leslie Hendrix, Suzanne Aisen, Paul Gaynor, Siobhan Sheikhi, Ali Taekema, Diana G. Verhey, Frans R. Nemni, Raffaello Nobili, Flavio Franceschi, Massimo Frisoni, Giovanni Zanetti, Orazio Konsta, Anastasia Anastasios, Orologas Nenopoulou, Styliani Tsolaki-Tagaraki, Fani Pakaski, Magdolna Dereeper, Olivier de la Sayette, Vincent Sénéchal, Olivier Lavenu, Isabelle Devendeville, Agnés Calais, Gauthier Crawford, Fiona Mullan, Michael 2018-10-15T09:46:34Z 2018-10-15T09:46:34Z 2018
dc.description peer-reviewed en_US
dc.description.abstract Background This study reports the findings of the first large-scale Phase III investigator-driven clinical trial to slow the rate of cognitive decline in Alzheimer disease with a dihydropyridine (DHP) calcium channel blocker, nilvadipine. Nilvadipine, licensed to treat hypertension, reduces amyloid production, increases regional cerebral blood flow, and has demonstrated anti-inflammatory and anti-tau activity in preclinical studies, properties that could have diseasemodifying effects for Alzheimer disease. We aimed to determine if nilvadipine was effective in slowing cognitive decline in subjects with mild to moderate Alzheimer disease. Methods and findings NILVAD was an 18-month, randomised, placebo-controlled, double-blind trial that randomised participants between 15 May 2013 and 13 April 2015. The study was conducted at 23 academic centres in nine European countries. Of 577 participants screened, 511 were eligible and were randomised (258 to placebo, 253 to nilvadipine). Participants took a trial treatment capsule once a day after breakfast for 78 weeks. Participants were aged >50 years, meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease Criteria (NINCDS-ADRDA) for diagnosis of probable Alzheimer disease, with a Standardised Mini-Mental State Examination (SMMSE) score of 12 and <27. Participants were randomly assigned to 8 mg sustained-release nilvadipine or matched placebo. The a priori defined primary outcome was progression on the Alzheimer's Disease Assessment Scale Cognitive Subscale-12 (ADAS-Cog 12) in the modified intention-to-treat (mITT) population (n = 498), with the Clinical Dementia Rating Scale sum of boxes (CDR-sb) as a gated co-primary outcome, eligible to be promoted to primary end point conditional on a significant effect on the ADAS-Cog 12. The analysis set had a mean age of 73 years and was 62% female. Baseline demographic and Alzheimer disease_specific characteristics were similar between treatment groups, with reported mean of 1.7 years since diagnosis and mean SMMSE of 20.4. The prespecified primary analyses failed to show any treatment benefit for nilvadipine on the co-primary outcome (p = 0.465). Decline from baseline in ADASCog 12 on placebo was 0.79 (95% CI, −0.07-1.64) at 13 weeks, 6.41 (5.33-7.49) at 52 weeks, and 9.63 (8.33-10.93) at 78 weeks and on nilvadipine was 0.88 (0.02-1.74) at 13 weeks, 5.75 (4.66-6.85) at 52 weeks, and 9.41 (8.09-10.73) at 78 weeks. Exploratory analyses of the planned secondary outcomes showed no substantial effects, including on the CDR-sb or the Disability Assessment for Dementia. Nilvadipine appeared to be safe and well tolerated. Mortality was similar between groups (3 on nilvadipine, 4 on placebo); higher counts of adverse events (AEs) on nilvadipine (1,129 versus 1,030), and serious adverse events (SAEs; 146 versus 101), were observed. There were 14 withdrawals because of AEs. Major limitations of this study were that subjects had established dementia and the likelihood that non-Alzheimer subjects were included because of the lack of biomarker confirmation of the presence of brain amyloid. Conclusions The results do not suggest benefit of nilvadipine as a treatment in a population spanning mild to moderate Alzheimer disease. en_US
dc.language.iso eng en_US
dc.publisher Public Library of Science en_US
dc.relation.ispartofseries PLoS Medicine;15(9):e1002660
dc.subject nilvadipine en_US
dc.subject mild en_US
dc.subject moderate en_US
dc.subject alzheimer en_US
dc.subject randomised controlled trial en_US
dc.title Nilvadipine in mild to moderate alzheimer disease: a randomised controlled trial en_US
dc.type info:eu-repo/semantics/article en_US
dc.type.supercollection all_ul_research en_US
dc.type.supercollection ul_published_reviewed en_US
dc.identifier.doi 10.1371/journal.pmed.1002660
dc.contributor.sponsor European Commission en_US
dc.contributor.sponsor UCLH NIHR Biomedical Research Centre, UK (RH) en_US
dc.contributor.sponsor Hauts-de-Freance Region, France (FP) en_US
dc.relation.projectid 279093 en_US
dc.rights.accessrights info:eu-repo/semantics/openAccess en_US
dc.internal.rssid 2870648

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