A Phase III Trial of Nilvadipine to Treat Alzheimer's Disease

Summary

Alzheimer's disease (AD) is an ever-increasing public health concern among the aging population and is the most common form of dementia affecting more than 15 million individuals worldwide and around 5 million Europeans. The direct and indirect costs of AD and other dementias amount to more than €440,000 million each year (www.alz.org, 2010). Even modest therapeutic advances that delay disease onset and progression could significantly reduce the global burden of the disease and the level of care required by patients. While there are symptomatic-based drug therapies available for AD, these medications do not prevent the disease process itself. There is therefore an imperative to develop new treatments for AD that have disease modifying effects. This double-blind placebo controlled study will test the efficacy and safety of nilvadipine in 500 subjects with mild to moderate AD over a treatment period of 18 months. There is a strong scientific rationale for this study: Nilvadipine, a licensed calcium channel enhances Aß clearance from brain and restores cortical perfusion in mouse models of AD. Nilvadipine is safe and well tolerated in AD patients and clinical studies with this medication have shown stabilization of cognitive decline and reduced incidence of AD, pointing to both symptomatic and disease modifying benefits. Male and female patients with mild to moderate AD aged between 50 and 90 with a range of medical morbidities and frailty will be included in the study. If this trial is successful, nilvadipine would represent an advance in the treatment of AD patients and would have a major impact on the health and social care costs incurred in Europe by this neurodegenerative disorder. Furthermore, the creation of the NILVAD network will support future clinical trials and research innovation in AD across Europe.

Timeline

Start

2013-04-24

Primary completion

2016-12-16

Completion

2016-12-16

Publications

• Background Brogden RN, McTavish D. Nilvadipine. A review of its pharmacodynamic and pharmacokinetic properties, therapeutic use in hypertension and potential in cerebrovascular disease and angina. Drugs Aging. 1995 Feb;6(2):150-71. doi: 10.2165/00002512-199506020-00007.
• Background Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-83. doi: 10.1016/0021-9681(87)90171-8.
• Background Facchinetti F, Fasolato C, Del Giudice E, Burgo A, Furegato S, Fusco M, Basso E, Seraglia R, D'Arrigo A, Leon A. Nimodipine selectively stimulates beta-amyloid 1-42 secretion by a mechanism independent of calcium influx blockage. Neurobiol Aging. 2006 Feb;27(2):218-27. doi: 10.1016/j.neurobiolaging.2005.02.006.
• Background Fleckenstein A. Specific pharmacology of calcium in myocardium, cardiac pacemakers, and vascular smooth muscle. Annu Rev Pharmacol Toxicol. 1977;17:149-66. doi: 10.1146/annurev.pa.17.040177.001053. No abstract available.
• Background Forette F, Seux ML, Staessen JA, Thijs L, Birkenhager WH, Babarskiene MR, Babeanu S, Bossini A, Gil-Extremera B, Girerd X, Laks T, Lilov E, Moisseyev V, Tuomilehto J, Vanhanen H, Webster J, Yodfat Y, Fagard R. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet. 1998 Oct 24;352(9137):1347-51. doi: 10.1016/s0140-6736(98)03086-4.
• Background Forette F, Seux ML, Staessen JA, Thijs L, Babarskiene MR, Babeanu S, Bossini A, Fagard R, Gil-Extremera B, Laks T, Kobalava Z, Sarti C, Tuomilehto J, Vanhanen H, Webster J, Yodfat Y, Birkenhager WH; Systolic Hypertension in Europe Investigators. The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Arch Intern Med. 2002 Oct 14;162(18):2046-52. doi: 10.1001/archinte.162.18.2046.
• Background Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, Seeman T, Tracy R, Kop WJ, Burke G, McBurnie MA; Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001 Mar;56(3):M146-56. doi: 10.1093/gerona/56.3.m146.
• Background Furuichi Y, Takakura S, Satoh H, Mori J, Kohsaka M. The effect of nilvadipine, a dihydropyridine type calcium channel blocker, on local cerebral blood flow in rats. Jpn J Pharmacol. 1992 Apr;58(4):457-60. doi: 10.1254/jjp.58.457.
• Background Gelinas I, Gauthier L, McIntyre M, Gauthier S. Development of a functional measure for persons with Alzheimer's disease: the disability assessment for dementia. Am J Occup Ther. 1999 Sep-Oct;53(5):471-81. doi: 10.5014/ajot.53.5.471.
• Background Hanyu H, Hirao K, Shimizu S, Sato T, Kiuchi A, Iwamoto T. Nilvadipine prevents cognitive decline of patients with mild cognitive impairment. Int J Geriatr Psychiatry. 2007 Dec;22(12):1264-6. doi: 10.1002/gps.1851. No abstract available.
• Background Inouye M, Mio T, Sumino K. Nilvadipine protects low-density lipoprotein cholesterol from in vivo oxidation in hypertensive patients with risk factors for atherosclerosis. Eur J Clin Pharmacol. 2000 Apr;56(1):35-41. doi: 10.1007/s002280050717.
• Background Khachaturian AS, Zandi PP, Lyketsos CG, Hayden KM, Skoog I, Norton MC, Tschanz JT, Mayer LS, Welsh-Bohmer KA, Breitner JC. Antihypertensive medication use and incident Alzheimer disease: the Cache County Study. Arch Neurol. 2006 May;63(5):686-92. doi: 10.1001/archneur.63.5.noc60013. Epub 2006 Mar 13.
• Background Kagawa H, Nomura S, Ozaki Y, Nagahama M, Fukuhara S. Effects of nilvadipine on cytokine-levels and soluble factors in collagen disease complicated with essential hypertension. Clin Exp Hypertens. 1999 Oct;21(7):1177-88. doi: 10.3109/10641969909052196.
• Background Lopez-Arrieta JM, Birks J. Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst Rev. 2002;(3):CD000147. doi: 10.1002/14651858.CD000147.
• Background Lubben J, Blozik E, Gillmann G, Iliffe S, von Renteln Kruse W, Beck JC, Stuck AE. Performance of an abbreviated version of the Lubben Social Network Scale among three European community-dwelling older adult populations. Gerontologist. 2006 Aug;46(4):503-13. doi: 10.1093/geront/46.4.503.
• Background Maxwell CJ, Hogan DB, Ebly EM. Calcium-channel blockers and cognitive function in elderly people: results from the Canadian Study of Health and Aging. CMAJ. 1999 Sep 7;161(5):501-6.
• Background McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology. 1984 Jul;34(7):939-44. doi: 10.1212/wnl.34.7.939.
• Background Mohs RC, Rosen WG, Davis KL. The Alzheimer's disease assessment scale: an instrument for assessing treatment efficacy. Psychopharmacol Bull. 1983;19(3):448-50. No abstract available.
• Background Molloy DW, Standish TI. A guide to the standardized Mini-Mental State Examination. Int Psychogeriatr. 1997;9 Suppl 1:87-94; discussion 143-50. doi: 10.1017/s1041610297004754.
• Background Morris JC. The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology. 1993 Nov;43(11):2412-4. doi: 10.1212/wnl.43.11.2412-a. No abstract available.
• Background Morris JC, Heyman A, Mohs RC, Hughes JP, van Belle G, Fillenbaum G, Mellits ED, Clark C. The Consortium to Establish a Registry for Alzheimer's Disease (CERAD). Part I. Clinical and neuropsychological assessment of Alzheimer's disease. Neurology. 1989 Sep;39(9):1159-65. doi: 10.1212/wnl.39.9.1159.
• Background Ogasawara K, Noda A, Yasuda S, Kobayashi M, Yukawa H, Ogawa A. Effect of calcium antagonist on cerebral blood flow and oxygen metabolism in patients with hypertension and chronic major cerebral artery occlusion: a positron emission tomography study. Nucl Med Commun. 2003 Jan;24(1):71-6. doi: 10.1097/00006231-200301000-00017.
• Background Ohtsuka M, Ono T, Hiroi J, Esumi K, Kikuchi H, Kumada S. Comparison of the cardiovascular effect of FR34235, a new dihydropyridine, with other calcium antagonists. J Cardiovasc Pharmacol. 1983 Nov-Dec;5(6):1074-82. doi: 10.1097/00005344-198311000-00024.
• Background Parry SW, Steen N, Baptist M, Fiaschi KA, Parry O, Kenny RA. Cerebral autoregulation is impaired in cardioinhibitory carotid sinus syndrome. Heart. 2006 Jun;92(6):792-7. doi: 10.1136/hrt.2004.053348. Epub 2006 Jan 31.
• Background Rosenthal J. Nilvadipine: profile of a new calcium antagonist. An overview. J Cardiovasc Pharmacol. 1994;24 Suppl 2:S92-107.
• Background Shimamoto H, Shimamoto Y. Nilvadipine increases cerebral blood flow in elderly hypertensives: comparison with nifedipine. J Hum Hypertens. 1995 Apr;9(4):271-9.
• Background Tollefson GD. Short-term effects of the calcium channel blocker nimodipine (Bay-e-9736) in the management of primary degenerative dementia. Biol Psychiatry. 1990 May 15;27(10):1133-42. doi: 10.1016/0006-3223(90)90050-c.
• Background Verghese J, Lipton RB, Katz MJ, Hall CB, Derby CA, Kuslansky G, Ambrose AF, Sliwinski M, Buschke H. Leisure activities and the risk of dementia in the elderly. N Engl J Med. 2003 Jun 19;348(25):2508-16. doi: 10.1056/NEJMoa022252.
• Background Yasar S, Corrada M, Brookmeyer R, Kawas C. Calcium channel blockers and risk of AD: the Baltimore Longitudinal Study of Aging. Neurobiol Aging. 2005 Feb;26(2):157-63. doi: 10.1016/j.neurobiolaging.2004.03.009.
• Dyer AH, Lawlor B, Kennelly SP; NILVAD Study Group. Gait speed, cognition and falls in people living with mild-to-moderate Alzheimer disease: data from NILVAD. BMC Geriatr. 2020 Mar 30;20(1):117. doi: 10.1186/s12877-020-01531-w.
• Abdullah L, Crawford F, Tsolaki M, Borjesson-Hanson A, Olde Rikkert M, Pasquier F, Wallin A, Kennelly S, Ait-Ghezala G, Paris D, Hendrix S, Blennow K, Lawlor B, Mullan M. The Influence of Baseline Alzheimer's Disease Severity on Cognitive Decline and CSF Biomarkers in the NILVAD Trial. Front Neurol. 2020 Mar 6;11:149. doi: 10.3389/fneur.2020.00149. eCollection 2020.
• de Heus RAA, Olde Rikkert MGM, Tully PJ, Lawlor BA, Claassen JAHR; NILVAD Study Group. Blood Pressure Variability and Progression of Clinical Alzheimer Disease. Hypertension. 2019 Nov;74(5):1172-1180. doi: 10.1161/HYPERTENSIONAHA.119.13664. Epub 2019 Sep 23.
• de Jong DLK, de Heus RAA, Rijpma A, Donders R, Olde Rikkert MGM, Gunther M, Lawlor BA, van Osch MJP, Claassen JAHR. Effects of Nilvadipine on Cerebral Blood Flow in Patients With Alzheimer Disease. Hypertension. 2019 Aug;74(2):413-420. doi: 10.1161/HYPERTENSIONAHA.119.12892. Epub 2019 Jun 17.
• de Heus RAA, Donders R, Santoso AMM, Olde Rikkert MGM, Lawlor BA, Claassen JAHR; Nilvad Study Group. Blood Pressure Lowering With Nilvadipine in Patients With Mild-to-Moderate Alzheimer Disease Does Not Increase the Prevalence of Orthostatic Hypotension. J Am Heart Assoc. 2019 May 21;8(10):e011938. doi: 10.1161/JAHA.119.011938.
• Lawlor B, Segurado R, Kennelly S, Olde Rikkert MGM, Howard R, Pasquier F, Borjesson-Hanson A, Tsolaki M, Lucca U, Molloy DW, Coen R, Riepe MW, Kalman J, Kenny RA, Cregg F, O'Dwyer S, Walsh C, Adams J, Banzi R, Breuilh L, Daly L, Hendrix S, Aisen P, Gaynor S, Sheikhi A, Taekema DG, Verhey FR, Nemni R, Nobili F, Franceschi M, Frisoni G, Zanetti O, Konsta A, Anastasios O, Nenopoulou S, Tsolaki-Tagaraki F, Pakaski M, Dereeper O, de la Sayette V, Senechal O, Lavenu I, Devendeville A, Calais G, Crawford F, Mullan M; NILVAD Study Group. Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial. PLoS Med. 2018 Sep 24;15(9):e1002660. doi: 10.1371/journal.pmed.1002660. eCollection 2018 Sep.

Drugs

Indications