TY - JOUR
T1 - Nilvadipine in mild to moderate Alzheimer disease
T2 - A randomised controlled trial
AU - for the NILVAD Study Group
AU - Lawlor, Brian
AU - Segurado, Ricardo
AU - Kennelly, Sean
AU - Olde Rikkert, Marcel G.M.
AU - Howard, Robert
AU - Pasquier, Florence
AU - Börjesson-Hanson, Anne
AU - Tsolaki, Magda
AU - Lucca, Ugo
AU - Molloy, D. William
AU - Coen, Robert
AU - Riepe, Matthias W.
AU - Kálmán, János
AU - Kenny, Rose Anne
AU - Cregg, Fiona
AU - O'Dwyer, Sarah
AU - Walsh, Cathal
AU - Adams, Jessica
AU - Banzi, Rita
AU - Breuilh, Laetitia
AU - Daly, Leslie
AU - Hendrix, Suzanne
AU - Aisen, Paul
AU - Gaynor, Siobhan
AU - Sheikhi, Ali
AU - Taekema, Diana G.
AU - Verhey, Frans R.
AU - Nemni, Raffaello
AU - Nobili, Flavio
AU - Franceschi, Massimo
AU - Frisoni, Giovanni
AU - Zanetti, Orazio
AU - Konsta, Anastasia
AU - Anastasios, Orologas
AU - Nenopoulou, Styliani
AU - Tsolaki-Tagaraki, Fani
AU - Pakaski, Magdolna
AU - Dereeper, Olivier
AU - de la Sayette, Vincent
AU - Sénéchal, Olivier
AU - Lavenu, Isabelle
AU - Devendeville, Agnès
AU - Calais, Gauthier
AU - Crawford, Fiona
AU - Mullan, Michael
N1 - Publisher Copyright:
© 2018 Lawlor et al. http://creativecommons.org/licenses/by/4.0/.
PY - 2018/9
Y1 - 2018/9
N2 - 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 disease-modifying 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 ADAS-Cog 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. Trial registration: Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.
AB - 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 disease-modifying 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 ADAS-Cog 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. Trial registration: Clinicaltrials.gov NCT02017340, EudraCT number 2012-002764-27.
UR - http://www.scopus.com/inward/record.url?scp=85054619470&partnerID=8YFLogxK
U2 - 10.1371/journal.pmed.1002660
DO - 10.1371/journal.pmed.1002660
M3 - Article
C2 - 30248105
AN - SCOPUS:85054619470
SN - 1549-1277
VL - 15
JO - PLoS Medicine
JF - PLoS Medicine
IS - 9
M1 - e1002660
ER -