Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial.
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...
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2018-09-01
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| Series: | PLoS Medicine |
| Online Access: | http://europepmc.org/articles/PMC6152871?pdf=render |
| _version_ | 1811269091395108864 |
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| author | Brian Lawlor Ricardo Segurado Sean Kennelly Marcel G M Olde Rikkert Robert Howard Florence Pasquier Anne Börjesson-Hanson Magda Tsolaki Ugo Lucca D William Molloy Robert Coen Matthias W Riepe János Kálmán Rose Anne Kenny Fiona Cregg Sarah O'Dwyer Cathal Walsh Jessica Adams Rita Banzi Laetitia Breuilh Leslie Daly Suzanne Hendrix Paul Aisen Siobhan Gaynor Ali Sheikhi Diana G Taekema Frans R Verhey Raffaello Nemni Flavio Nobili Massimo Franceschi Giovanni Frisoni Orazio Zanetti Anastasia Konsta Orologas Anastasios Styliani Nenopoulou Fani Tsolaki-Tagaraki Magdolna Pakaski Olivier Dereeper Vincent de la Sayette Olivier Sénéchal Isabelle Lavenu Agnès Devendeville Gauthier Calais Fiona Crawford Michael Mullan NILVAD Study Group |
| author_facet | Brian Lawlor Ricardo Segurado Sean Kennelly Marcel G M Olde Rikkert Robert Howard Florence Pasquier Anne Börjesson-Hanson Magda Tsolaki Ugo Lucca D William Molloy Robert Coen Matthias W Riepe János Kálmán Rose Anne Kenny Fiona Cregg Sarah O'Dwyer Cathal Walsh Jessica Adams Rita Banzi Laetitia Breuilh Leslie Daly Suzanne Hendrix Paul Aisen Siobhan Gaynor Ali Sheikhi Diana G Taekema Frans R Verhey Raffaello Nemni Flavio Nobili Massimo Franceschi Giovanni Frisoni Orazio Zanetti Anastasia Konsta Orologas Anastasios Styliani Nenopoulou Fani Tsolaki-Tagaraki Magdolna Pakaski Olivier Dereeper Vincent de la Sayette Olivier Sénéchal Isabelle Lavenu Agnès Devendeville Gauthier Calais Fiona Crawford Michael Mullan NILVAD Study Group |
| author_sort | Brian Lawlor |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T21:34:47Z |
| format | Article |
| id | doaj.art-96fe8e60d2d245c38445e16c3151fb36 |
| institution | Directory Open Access Journal |
| issn | 1549-1277 1549-1676 |
| language | English |
| last_indexed | 2024-04-12T21:34:47Z |
| publishDate | 2018-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Medicine |
| spelling | doaj.art-96fe8e60d2d245c38445e16c3151fb362022-12-22T03:15:55ZengPublic Library of Science (PLoS)PLoS Medicine1549-12771549-16762018-09-01159e100266010.1371/journal.pmed.1002660Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial.Brian LawlorRicardo SeguradoSean KennellyMarcel G M Olde RikkertRobert HowardFlorence PasquierAnne Börjesson-HansonMagda TsolakiUgo LuccaD William MolloyRobert CoenMatthias W RiepeJános KálmánRose Anne KennyFiona CreggSarah O'DwyerCathal WalshJessica AdamsRita BanziLaetitia BreuilhLeslie DalySuzanne HendrixPaul AisenSiobhan GaynorAli SheikhiDiana G TaekemaFrans R VerheyRaffaello NemniFlavio NobiliMassimo FranceschiGiovanni FrisoniOrazio ZanettiAnastasia KonstaOrologas AnastasiosStyliani NenopoulouFani Tsolaki-TagarakiMagdolna PakaskiOlivier DereeperVincent de la SayetteOlivier SénéchalIsabelle LavenuAgnès DevendevilleGauthier CalaisFiona CrawfordMichael MullanNILVAD Study GroupBACKGROUND: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.http://europepmc.org/articles/PMC6152871?pdf=render |
| spellingShingle | Brian Lawlor Ricardo Segurado Sean Kennelly Marcel G M Olde Rikkert Robert Howard Florence Pasquier Anne Börjesson-Hanson Magda Tsolaki Ugo Lucca D William Molloy Robert Coen Matthias W Riepe János Kálmán Rose Anne Kenny Fiona Cregg Sarah O'Dwyer Cathal Walsh Jessica Adams Rita Banzi Laetitia Breuilh Leslie Daly Suzanne Hendrix Paul Aisen Siobhan Gaynor Ali Sheikhi Diana G Taekema Frans R Verhey Raffaello Nemni Flavio Nobili Massimo Franceschi Giovanni Frisoni Orazio Zanetti Anastasia Konsta Orologas Anastasios Styliani Nenopoulou Fani Tsolaki-Tagaraki Magdolna Pakaski Olivier Dereeper Vincent de la Sayette Olivier Sénéchal Isabelle Lavenu Agnès Devendeville Gauthier Calais Fiona Crawford Michael Mullan NILVAD Study Group Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial. PLoS Medicine |
| title | Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial. |
| title_full | Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial. |
| title_fullStr | Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial. |
| title_full_unstemmed | Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial. |
| title_short | Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial. |
| title_sort | nilvadipine in mild to moderate alzheimer disease a randomised controlled trial |
| url | http://europepmc.org/articles/PMC6152871?pdf=render |
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