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BMJ Open 2014;4:e006364 doi:10.1136/bmjopen-2014-006364 Geriatric medicine Protocol NILVAD protocol: a European multicentre double-blind placebo-controlled trial of nilvadipine in mild- to-moderate Alzheimer's disease Brian Lawlor1, Sean Kennelly1, Sarah O'Dwyer1, Fiona Cregg2, Cathal Walsh2, Robert Coen1, Rose Anne Kenny1, Robert Howard3, Caroline Murphy3, Jessica Adams3, Leslie Daly4, Ricardo Segurado4, Siobhan Gaynor5, Fiona Crawford6, Michael Mullan6, Ugo Lucca7, Rita Banzi7, Florence Pasquier8, Laetitia Breuilh8, Matthias Riepe9, Janos Kalman10, Anders Wallin11, Anne Borjesson11, William Molloy12, Magda Tsolaki13, Marcel Olde Rikkert14 + Author Affiliations 1Mercer's Institute for Research on Ageing, St. James's Hospital, Dublin, Ireland 2Trinity College Dublin (TCD), Dublin, Ireland 3King's College London (KCL), London, UK 4University College Dublin (UCD), Dublin, Ireland 5Molecular Medicine Ireland (MMI), Dublin, Ireland 6Archer Pharmaceuticals Inc, 2040 Whitefield Avenue, Sarasota, Florida, USA 7IRCCS—Istituto di Ricerche Farmacologiche “Mario Negri” (IRFMN), Milan, Italy 8Centre Hospitalier Regional et Universitaire de Lille (CHRU- LILLE), Lille, France 9Universitaet Ulm, (UULM), Ulm, Germany 10Szegedi Tudomanyegyetem (SZEGED), Szeged, Hungary 11Göteborgs Universitet (UGOT), Gothenburg, Sweden 12University College Cork (UCC), Cork, Ireland 13Aristotle University of Thessaloniki (AUTH), Greece 14Radboud Alzheimer Centre; Radboud University Medical Centre, Nijmegen, The Netherlands Correspondence to Prof. Brian Lawlor; [email protected] Received 26 August 2014 Accepted 5 September 2014 Published 9 October 2014 Next Section Abstract Introduction This study is a European multicentre, randomised, double-blind, placebo-controlled trial investigating the efficacy and safety of nilvadipine as a disease course modifying treatment for mild- to-moderate Alzheimer's disease (AD) in a phase III study that will run for a period of 82 weeks with a treatment period of 78 weeks. Methods and analysis Adult patients, males and females over 50 years with mild-to-moderate AD as defined by the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease and Related Disorders Association (NINCDS-ADRDA) criteria, will be included in the study. It aims to recruit a total of 500 patients with AD; 250 in the nilvadipine group and 250 in the placebo group. Participants will be randomised to receive nilvadipine, an 8 mg overencapsulated, sustained release capsule, or a matching overencapsulated placebo (sugar pill) for a period of 78 weeks of treatment. The primary efficacy outcome measure in this study is the change in cognitive function as assessed by the Alzheimer's disease Assessment Scale (ADAS-Cog 12) from baseline to the end of treatment duration (78 weeks). There are two key secondary outcome measures, the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb) and the Disability Assessment for Dementia (DAD). If a statistically significant effect is seen in the primary outcome, CDR-sb will be considered to be a coprimary end point and only the DAD will contribute to the secondary outcome analysis. Ethics and dissemination The study and all subsequent amendments have received ethical approval within each participating country according to national regulations. Each participant will provide written consent to participate in the study. All participants will remain anonymised throughout and the results of the study will be published in an international peer-reviewed journal. Trial registration number EUDRACT Reference Number: 2012-002764-27. GERIATRIC MEDICINE Strengths and limitations of this study Large European multicentre double-blind, randomised placebo-controlled trial. Investigator driven. Testing a repositioned medication with a proven safety profile and approved for the treatment of hypertension. Does not test the disease modifying efficacy and safety of nilvadipine at the predementia stage. Previous SectionNext Section Introduction The current disappointing state of clinical trials aimed at advancing therapeutic interventions for Alzheimer's disease (AD) has necessitated the need for development of novel strategies that target multiple aspects of the pathogenic process in this neurodegenerative condition. Furthermore, ideally, any novel drugs or compounds tested would have a demonstrated safety profile in order to expedite the path to clinical application. Calcium antagonists or calcium channel blockers (CCBs) were first introduced over 25 years ago as coronary vasodilators for the treatment of coronary heart disease, and have since achieved notable recognition in the treatment of arterial hypertension.1 Nilvadipine (trade name: Nivadil), a dihydropyridine (DHP) calcium channel antagonist, is currently licensed to treat patients with hypertension.2 However, recent research has highlighted other properties of certain CCBs, including nilvadipine, suggesting that they are protective not just against stroke-related dementia, but also independently against AD.3 Research to date has suggested that the AD preventive effect of DHP CCBs, may not be mediated through their antihypertensive effects, but rather via an anti-β-amyloid (Aβ) mechanism where the accumulation of Aβ in the brain is reduced by altering Aβ production in the brain and Aβ clearance across the blood–brain barrier (BBB). Paris et al investigated the effects of a number of commonly used antihypertensive DHPs and non-DHPs on Aβ production both in vitro and in vivo and found that not all DHPs are equal. Nilvadipine and amlodipine were found to significantly lower Aβ40 as well as Aβ42 production in vitro, however, other DHPs and non-DHPs had little effect or even increased Aβ40 and Aβ42 production in vitro. The in vivo studies using transgenic mouse models of AD (Tg PS1/APPsw) highlighted nilvadipine reduced levels of Aβ in the brain and, furthermore, nilvadipine enhanced Aβ clearance across the BBB. In addition to these properties, nilvadipine has shown efficacy against a broad range of AD pathological mechanisms, including τ-phosphorylation, reduced cerebral blood flow and neuroinflammation.3 Studies have found that nilvadipine is distributed extensively throughout the body, including the brain and has been shown to have a cerebrocirculatory enhancing effect.4 Nilvadipine has also been shown to protect low-density lipoprotein cholesterol from in vivo oxidation in patients with hypertension with high risk of atherosclerosis and to inhibit the generation of cytokines derived from activated T lymphocytes in collagen disease complicated with essential hypertension.5 ,6 Several epidemiological studies with different calcium channel antagonists have been conducted to determine their potential usefulness in the management of AD. In the Systolic Hypertension in Europe (Syst-Eur) trial, which involved active treatment with the DHP CCB nitrendipine in over 2400 patients, there was a 55% reduction in the incidence of AD.7 The Baltimore Longitudinal Study of Ageing also found a strong trend towards reduced relative risk of AD in patients treated with DHP CCBs, with no lowered risk observed in the non-DHP CCB treatment group.8 Furthermore, nilvadipine has been shown to have favourable effects on cognitive function with stabilisation of cognitive decline and reduced conversion to AD in patients with hypertension with mild cognitive impairment.9 A study by Kennelly et al10 provided preliminary evidence suggesting the potential efficacy in the treatment of AD. A 6-week open label study demonstrated that nilvadipine was well tolerated in patients with AD.11 A nilvadipine slow release 8 mg formulation did not reduce blood pressure (BP) in non-hypertensive patients with AD, but appropriately lowered BP in hypertensive cases. No patient started on nilvadipine requested or required discontinuation of the medication throughout this study, highlighting that nilvadipine is well tolerated in patients with AD and has demonstrated safety as a licensed antihypertensive treatment. In summary, this study will investigate the safety and efficacy of nilvadipine as a disease-modifying treatment in patients with mild-to-moderate AD over a period of 18 months across nine countries in Europe including Ireland, Germany, Greece, France, Holland, Hungary, Italy, Sweden and the UK. Overall, the aim is to build on the initial studies of nilvadipine as a treatment for AD by investigating its efficacy and establish its safety profile in a phase III double-blind, randomised, placebo-controlled trial. Previous SectionNext Section Methods and analysis Trial design This is a multicentre, randomised, double-blind, placebo-controlled study of nilvadipine compared with placebo. Eligible patients will be randomly assigned to receive 8 mg of nilvadipine or placebo daily for 78 weeks of treatment. Patients will initially undergo a screening assessment to confirm eligibility. This will be followed by a baseline visit (week 0), when each patient is randomised and will receive the first dose of study medication. Patients will then undergo assessments at weeks 6, 13, 26, 39, 52, 65 and 78 (±7 days) after beginning treatment. A final follow-up assessment will be undertaken at 82