Abstract
Objective
To compare the long-term efficacy and safety of galantamine 24 mg/day and donepezil 10 mg/day in patients with Alzheimer’s disease.
Patients and Study Design
This was a rater-blinded, randomised, parallel-group multicentre study (18 outpatient clinics) in the UK. 182 patients (69 male, 113 female) with Alzheimer’s disease were randomised to galantamine (n = 94) or donepezil (n = 88) for 52 weeks.
Main outcome measures
The effects of galantamine and donepezil on function using the Bristol Activities of Daily Living Scale (BrADL); cognition using the Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog/11); behaviour using the Neuropsychiatric Inventory (NPI); caregiver burden using the Screen for Caregiver Burden; and safety were assessed.
Results
BrADL total scores showed no significant difference between treatment groups in mean change from baseline to week 52. In the total population, in terms of cognition, galantamine patients’ scores on the MMSE at week 52 did not differ significantly from baseline (−0.52 ± 0.39, p < 0.5 vs baseline), whereas donepezil patients’ scores deteriorated significantly from baseline (−1.58 ± 0.42, p < 0.0005 vs baseline). The between-group difference in MMSE change, which showed a trend for superiority of galantamine, did not reach statistical significance (p < 0.1). In the ADAS-cog/11 analysis, between-group differences for the total population were not significant, whereas galantamine-treated patients with MMSE scores of 12–18 demonstrated an increase (worsening) in the ADAS-cog/11 score of 1.61 ± 0.80 versus baseline, compared with an increase of 4.08 ± 0.84 for patients treated with donepezil, with a significant between-group difference in favour of galantamine (p ≤ 0.05). More caregivers of patients receiving galantamine reported reductions in burden compared with donepezil. Changes from baseline in NPI were similar for both treatments.
Both treatments were well tolerated; most adverse events were transient and of mild-to-moderate intensity, and were consistent with the findings of previous clinical trials.
Conclusions
Significant advantages were found in the treatment response to galantamine (versus donepezil) on cognition as measured by response rates on the MMSE and ADAS-cog/11.
Similar content being viewed by others
References
Levin ED. Nicotinic systems and cognitive function. Psychopharmacology (Berl) 1992; 108: 417–31
Levin ED, Simon BB. Nicotinic acetylcholine involvement in cognitive function in animals. Psychopharmacology (Berl) 1998; 138: 217–30
Raskind MA, Peskind ER, Wessel T, et al. Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. Neurology 2000; 54: 2261–8
Tariot PN, Solomon PR, Morris JC, et al. A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology 2000; 54: 2269–76
Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of galantamine in patients with mild to moderate Alzheimer’s disease: multicentre randomised controlled trial. BMJ 2000; 321: 1445–9
Rockwood K, Mintzer J, Truyen L, et al. Effects of a flexible galantamine dose in Alzheimer’s disease: a randomised, controlled trial. J Neurol Neurosurg Psychiatry 2001; 71: 589–95
Rogers SL, Farlow MR, Doody RS, et al. A 24-week, doubleblind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Donepezil Study Group. Neurology 1998; 50: 136–45
Rogers SL, Doody RS, Mohs RC, et al. Donepezil improves cognition and global function in Alzheimer disease: a 15-week, double-blind, placebo-controlled study. Donepezil Study Group. Arch Intern Med 1998; 158: 1021–31
Winblad B, Engedal K, Soininen H, et al. A 1-year, randomized, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001; 57: 489–95
Corey-Bloom J, Anand R, Veach J, for the ENA 713 B352 Study Group. A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer. Int J Geriatr Psychopharmacol 1998; 1: 55–65
Rosler M, Anand R, Cicin-Sain A, et al. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: international randomised controlled trial. BMJ 1999; 318: 633–8
Reminyl® [prescribing information]. Titusville (NJ): Janssen Pharmaceutica Products, L.P., 2001
Mohs RC, Doody RS, Morris JC, et al. A 1-year, placebocontrolled preservation of function survival study of donepezil in AD patients. Neurology 2001; 57: 481–8
Stern Y, Tang MX, Albert MS, et al. Predicting time to nursing home care and death in individuals with Alzheimer disease. JAMA 1997; 277: 806–12
Maelicke A, Albuquerque EX. Allosteric modulation of nicotinic acetylcholine receptors as a treatment strategy for Alzheimer’s disease. Eur J Pharmacol 2000; 393: 165–70
Albuquerque EX, Santos MD, Alkondon M, et al. Modulation of nicotinic receptor activity in the central nervous system: a novel approach to the treatment of Alzheimer disease. Alzheimer Dis Assoc Disord 2001; 15(Suppl 1): S19–25
Maelicke A. Allosteric modulation of nicotinic receptors as a treatment strategy for Alzheimer’s disease. Dement Geriatr Cogn Disord 2000; 11(Suppl 1): 11–8
Zhou FM, Liang Y, Dani JA. Endogenous nicotinic cholinergic activity regulates dopamine release in the striatum. Nat Neurosci 2001; 4: 1224–9
Perry RJ, Hodges JR. Attention and executive deficits in Alzheimer’s disease. A critical review. Brain 1999; 122: 383–404
Perry RJ, Hodges JR. Relationship between functional and neuropsychological performance in early Alzheimer disease. Alzheimer Dis Assoc Disord 2000; 14: 1–10
Blesa R. Galantamine: therapeutic effects beyond cognition. Dement Geriatr Cogn Disord 2000; 11(Suppl 1): 28–34
Thomsen T, Kewitz H. Selective inhibition of human acetylcholinesterase by galanthamine in vitro and in vivo. Life Sci 1990; 46: 1553–8
Wilkinson D, Murray J. Galantamine: a randomized, doubleblind, dose comparison in patients with Alzheimer’s disease. Int J Geriatr Psychiatry 2001; 16: 852–7
Jann MW, Shirley KL, Small GW. Clinical pharmacokinetics and pharmacodynamics of cholinesterase inhibitors. Clin Pharmacokinet 2002; 41: 719–39
Rogers SL, Friedhoff LT. The efficacy and safety of donepezil in patients with Alzheimer’s disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial. The Donepezil Study Group. Dementia 1996; 7: 293–303
Burns A, Rossor M, Hecker J, et al. The effects of donepezil in Alzheimer’s disease — results from a multinational trial. Dement Geriatr Cogn Disord 1999; 10: 237–44
Wilkinson DG, Passmore AP, Bullock R, et al. A multinational, randomised, 12-week, comparative study of donepezil and rivastigmine in patients with mild to moderate Alzheimer’s disease. Int J Clin Pract 2002; 56: 441–6
Jones RW, Passmore P, Wetterberg P, et al. First head to head study comparing the tolerability and efficacy of donepezil and galantamine in Alzheimer’s disease [poster]. 7th International Geneva/Springfield Symposium on Advances in Alzheimer Therapy; 2002 Apr 3–6; Geneva, Switzerland
McKhann G, Drachman D, Folstein M, et al. 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; 34: 939–44
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–98
Feldman H, Sauter A, Donald A, et al. The Disability Assessment for Dementia Scale: a 12-month study of functional ability in mild to moderate severity Alzheimer disease. Alzheimer Dis Assoc Disord 2001; 15: 89–95
Ariceptsu™ [prescribing information]. London (UK): Eisai Ltd., 2002
Bucks RS, Ashworth DL, Wilcock GK, et al. Assessment of activities of daily living in dementia: development of the Bristol Activities of Daily Living Scale. Age Ageing 1996; 25: 113–20
Byrne LM, Wilson PM, Bucks RS, et al. The sensitivity to change over time of the Bristol Activities of Daily Living Scale in Alzheimer’s disease. Int J Geriatr Psychiatry 2000; 15: 656–61
Hills R, Gray R, Stowe R, et al. Drop-out bias undermines findings of improved functionality with cholinesterase inhibitors [poster]. International Conference on Alzheimer’s Disease and Related Disorders, 2002 Jul 20–25; Stockholm, Sweden
Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984; 141: 1356–64
Cummings JL, Mega M, Gray K, et al. The Neuropsychiatric Inventory: comprehensive assessment of psychopathology in dementia. Neurology 1994; 44: 2308–14
Vitaliano PP, Russo J, Young HM, et al. The screen for caregiver burden. Gerontologist 1991; 31: 76–83
Simpson PM, Surmon DJ, Wesnes KA, et al. The cognitive drug research computerized assessment system for demented patients: a validation study. Int J Geriatr Psychiatry 1991; 6: 95–102
National Institute for Clinical Excellence. Guidance on the use of donepezil, rivastigmine and galantamine for the treatment of Alzheimer’s disease. Technology Appraisal Guidance No. 19 [online]. Available from URL: http://www.nice.org.uk/pdf/ALZHEIMER_full_guidance.pdf
Feldman H, Gauthier S, Hecker J, et al. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer’s disease. Neurology 2001; 57: 613–20
Jones GM, Sahakian BJ, Levy R, et al. Effects of acute subcutaneous nicotine on attention, information processing and short-term memory in Alzheimer’s disease. Psycho-pharmacology (Berl) 1992; 108: 485–94
Granon S, Passetti F, Thomas KL, et al. Enhanced and impaired attentional performance after infusion of D1 dopaminergic receptor agents into rat prefrontal cortex. J Neurosci 2000; 20: 1208–15
Kawas CH, Clark CM, Farlow MR, et al. Clinical trials in Alzheimer disease: debate on the use of placebo controls. Alzheimer Dis Assoc Disord 1999; 13: 124–9
Acknowledgements
The principal investigators of this study were: I. McKeith, Newcastle-Upon-Tyne, UK; J. Haworth, Bristol, UK; D. Wilkinson, Southampton, UK; R.W. Jones, Bath, UK; A. Bayer, Penarth, UK; R.J. Smith, Bradford, UK; B. Lawlor, Dublin, Ireland; P. Crome, Stoke-on-Trent, UK; C. Bulpitt, London, UK; B. Boothman, Preston, UK; M. Evans, Chester, UK; A. Barker, Barton-on-Sea, UK; S. Simpson, Herrison, UK; A. O’Brien, Westcliff on Sea, UK; M. Doran, Fazakerley, UK; C.M. Bonthala, Northampton, UK; R. Bullock, Swindon, UK; and F.G. Inglis, Irvine, UK
Gordon Wilcock, Hilary Coles, Ian Howe and Roger Bullock assisted in trial design. Roger Bullock was an investigator in the trial. Ian Howe, Sean Lilienfeld, Luc Truyen, Hilary Coles and Young Zhu assisted in data collection. Gordon Wilcock, Ian Howes, Roger Bullock, Sean Lilienfeld, Luc Truyen and Young Zhu assisted in data analysis as well as preparation, review and final approval of the clinical trial results. All authors participated in the preparation, review and final approval of the manuscript. Young Zhu is the project statistician.
Activities related to study design, data collection and analysis, as well as preparation and review of the manuscript were funded in whole or in part by Janssen-Cilag UK, Janssen Pharmaceutica Products L.P. and Shire Pharmaceuticals Ltd. Ian Howe is an employee of Shire Pharmaceuticals Ltd; Hilary Coles is an employee of Janssen-Cilag UK; Sean Lilienfeld and Luc Truyen are employees of Janssen Pharmaceutica Products L.P.; Gordon Wilcock and Roger Bullock have received honoraria from various pharmaceutical companies for consulting and lectures.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wilcock, G., Howe, I., Coles, H. et al. A Long-Term Comparison of Galantamine and Donepezil in the Treatment of Alzheimer’s Disease. Drugs Aging 20, 777–789 (2003). https://doi.org/10.2165/00002512-200320100-00006
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002512-200320100-00006