Type

Journal Article

Authors

Michael Mullan
Fiona Crawford
Gauthier Calais
Agnés Devendeville
Isabelle Lavenu
Olivier Sénéchal
Vincent de la Sayette
Olivier Dereeper
Magdolna Pakaski
Fani Tsolaki-Tagaraki
and 35 others

Subjects

Pharmacology

Topics
moderate mild regional blood flow cognitive decline anti inflammatory randomised controlled trial clinical trial nilvadipine alzheimer large scale alzheimer disease

Nilvadipine in mild to moderate alzheimer disease: a randomised controlled trial (2018)

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.
Collections Ireland -> University of Limerick -> Research Institutes
Ireland -> University of Limerick -> Mathematics & Statistics
Ireland -> University of Limerick -> Faculty of Science and Engineering
Ireland -> University of Limerick -> Health Research Institute (HRI)
Ireland -> University of Limerick -> Departments Science and Engineering
Ireland -> University College Cork -> Research Institutes and Centres
Ireland -> University of Limerick -> MACSI - Mathematics Application Consortium for Science & Industry
Ireland -> University of Limerick -> Centres Science and Engineering
Ireland -> University College Cork -> Centre for Gerontology and Rehabilitation
Ireland -> University of Limerick -> Research Institutes, Centres and Units
Ireland -> University College Cork -> Centre for Gerontology and Rehabilitation - Journal Articles

Full list of authors on original publication

Michael Mullan, Fiona Crawford, Gauthier Calais, Agnés Devendeville, Isabelle Lavenu, Olivier Sénéchal, Vincent de la Sayette, Olivier Dereeper, Magdolna Pakaski, Fani Tsolaki-Tagaraki and 35 others

Experts in our system