www.thelancet.com/neurology Vol 8 January 2009 39 Articles Safety and efficacy of galantamine (Reminyl) in severe Alzheimer’s disease (the SERAD study): a randomised, placebo-controlled, double-blind trial Alistair Burns, Roberto Bernabei, Roger Bullock, Alfonso J Cruz Jentoft, Lutz Frölich, Christoph Hock, Minna Raivio, Eric Triau, Maurits Vandewoude, Anders Wimo, Elizabeth Came, Bart Van Baelen, Gerry L Hammond, Joop C van Oene, Susanne Schwalen Summary Background The efficacy of galantamine has been shown in patients with mild, moderate, and advanced moderate Alzheimer’s disease (AD). Here we report its efficacy in patients with severe AD. Methods Between December, 2003, and March, 2007, patients aged 84 (SD 6) years with severe AD (mini-mental state examination [MMSE] score 5–12 points), in a nursing home setting were randomly assigned to receive galantamine (n=207), titrated initially to 24 mg/day, or placebo (n=200). Co-primary efficacy measures for cognitive function and ability to undertake normal daily activities were the severe impairment battery (SIB) and the seven-item minimum data set-activities of daily living (MDS-ADL), respectively. Adverse events, vital signs, laboratory parameters, and electrocardiograms were monitored. This trial is registered with ClinicalTrials.gov, number NCT00216593. Findings 168 of 207 (81%) patients in the galantamine group and 161 of 200 (81%) in the placebo group completed the study. Mean SIB scores increased (improved) by 1·9 (95% CI –0·1 to 3·9) points with galantamine and decreased (worsened) by 3·0 (–5·6 to –0·5) points with placebo (between-group least squares mean difference 4·36, 1·3 to 7·5; p=0·006). Mean MDS-ADL self-performance score worsened by 1·2 (0·6 to 1·8) points and 1·6 (0·8 to 2·3) points, respectively (between-group least squares mean difference –0·41, –1·3 to 0·5; p=0·383). Nominally significant between-group differences in favour of galantamine occurred for the SIB domains of memory (p=0·006), praxis (p=0·010), and visuospatial ability (p=0.002), and for the MDS-ADL subitem locomotion on unit (p=0·021). 183 of 207 patients (88%) who received galantamine and 177 of 200 (89%) who received placebo had adverse events, which were mostly mild to moderate. Eight patients (4%) in the galantamine group and 21 patients (11%) in the placebo group died. ECG abnormalities were similar between the two groups. Interpretation Galantamine can be started and used safely in elderly patients with severe AD. Galantamine improved cognitive function but failed to significantly improve the co-primary parameter of overall activities of daily living. Funding Janssen-Cilag EMEA. Introduction Alzheimer’s disease (AD) is an age-related neuro- degenerative disorder that is increasing in prevalence as the population lives longer. 1 For diagnostic, treatment, and research purposes, various stages of Alzheimer’s disease (AD) can be defined to indicate the level of impairment during progression from mild to moderate and severe to terminal dementia. As the disease progresses, cognitive decline extends to include impairments in the ability to undertake basic activities of daily living, such as walking without assistance, bathing, and dressing. 2 Thus, as the severity of AD increases, so too does the burden on caregivers, which is an important predictor of the requirement for long-term inpatient care. 3 Furthermore, the provision of adequate care for patients with severe AD carries enormous costs. 4 Galantamine is a reversible inhibitor of cholinesterase and an allosteric-potentiating ligand of the nicotinic acetylcholine receptors. 5 Clinical trials of inhibitors of cholinesterase have focused on patients with mild and moderate AD; therefore, efficacy data in patients with severe AD are scarce. Patients with milder disease will, however, progress to severe AD, and 20% of patients with AD are estimated to have severe dementia at any given time. 6 The benefits of galantamine on cognitive function, activities of daily living, and behaviour in patients with mild to moderate AD have been shown in randomised controlled trials and confirmed in meta-analyses. 7,8 The efficacy of galantamine was also assessed in a subpopulation of patients with advanced moderate AD (baseline mini-mental state examination [MMSE] 9 score 10–12 points), with significant benefits on cognitive function compared with placebo, maintenance of functional ability, and delay of behavioural symptoms. 10 Similar benefits were seen in a pooled post hoc analysis of data from 12 months’ follow-up in two studies of patients with advanced moderate AD (MMSE ≤14 points or Alzheimer’s disease assessment scale-cognitive subscale [ADAS-cog] score >30 points). 11 Significant benefits have been reported on cognitive function, activities of daily living, and behaviour with donepezil, an inhibitor of cholinesterase with no nicotinic Lancet Neurol 2009; 8: 39–47 Published Online December 1, 2008 DOI:10.1016/S1474- 4422(08)70261-8 See Reflection and Reaction page 39 University of Manchester, Manchester, UK (A Burns MD); Università Cattolica del Sacro Cuore, Rome, Italy (R Bernabei MD); Kingshill Research Centre, Swindon, UK (R Bullock MD); Hospital Universitario Ramón y Cajal, Madrid, Spain (A J Cruz Jentoft MD); Central Institute for Mental Health, Mannheim, Germany (L Frölich MD); University of Zürich, Zürich, Switzerland (C Hock MD); Memory Research and Treatment Centers Finland-Medical Center Hemo, Lahti, Finland (M Raivio MD); RVT De Wingerd, Leuven, Belgium (E Triau MD); University of Antwerp, Antwerp, Belgium (M Vandewoude MD); Primary Care Nordanstig and ADRC, Karolinska Institutet, Stockholm, Sweden (A Wimo MD); Came Clinical Research, Devizes, UK (E Came PhD); SGS Life Sciences Services, Mechelen, Belgium (B Van Baelen MSc); Janssen- Cilag EMEA , Beerse, Belgium (G L Hammond BSc); Janssen- Cilag EMEA, Tilburg, Netherlands (J C van Oene PhD); University Witten/Herdecke, Witten, Germany (S Schwalen MD) Correspondence to: Alistair Burns, University of Manchester, University Place, Manchester M13 9PL, UK alistair.burns@manchester. ac.uk