Articles Donepezil in patients with severe Alzheimer’s disease: double-blind, parallel-group, placebo-controlled study Bengt Winblad, Lena Kilander, Sture Eriksson, Lennart Minthon, Stellan Båtsman, Anna-Lena Wetterholm, Catarina Jansson-Blixt, Anders Haglund, for the Severe Alzheimer’s Disease Study Group* Summary Background The cholinesterase inhibitor donepezil is used to treat mild-to-moderate Alzheimer’s disease. Its Lancet 2006; 367: 1057–65 efficacy in severe dementia has not been assessed and is controversial. Our aim was to ascertain the effectiveness Published Online of donepezil in patients with severe Alzheimer’s disease, by focusing primarily on cognition and activities of daily March 23, 2006 DOI:10.1016/S0140-6736(06) living. 68350-5 See Comment page 1031 Methods We did a 6-month, double-blind, parallel-group, placebo-controlled study in 248 patients with severe *Members listed at end of paper Alzheimer’s disease (mini mental state examination score 1–10) who were living in assisted care nursing homes ran Karolinska Institutet, by trained staff in Sweden. We assigned patients oral donepezil (5 mg per day for 30 days then up to 10 mg per day Alzheimer’s Disease Research thereafter, n=128) or matched placebo (n=120). Our primary endpoints were change from baseline to month 6 in the Center, Department of severe impairment battery (SIB) and modified Alzheimer’s Disease Cooperative Study activities of daily living Neurotec, Division of Geriatric inventory for severe Alzheimer’s disease (ADCS-ADL-severe). We analysed outcomes for patients with data at baseline Medicine, Karolinska University Hospital, Huddinge, 14186 and at one or more other timepoints (modified intent-to-treat population) with last observation carried forward used Stockholm, Sweden to replace missing data. (Prof B Winblad MD); Department of Public Health Findings 95 patients assigned donepezil and 99 patients assigned placebo completed the study. Patients treated with and Caring Sciences/Geriatrics, Uppsala University, Uppsala, donepezil improved more in SIB scores and declined less in ADCS-ADL-severe scores at 6 months after initiation of Sweden (L Kilander MD); treatment compared with baseline than did controls (least squares [LS] mean difference, 5·7, 95% CI 1·5–9·8; p=0·008, Section of Geriatric Medicine, and 1·7, 0·2–3·2; p=0·03, respectively). The incidence of adverse events was comparable between groups (donepezil Department of Community 82% [n=105] vs placebo 76% [n=91]), with most being transient and mild or moderate in severity. More patients Medicine and Rehabilitation, Umeå University, Umeå, discontinued treatment because of adverse events in the donepezil group (n=20) than in the placebo group (n=8). Sweden (S Eriksson MD); Clinical Memory Research Unit, Interpretation Donepezil improves cognition and preserves function in individuals with severe Alzheimer’s disease Department of Clinical who live in nursing homes. Sciences, Malmö Lund University, Malmö, Sweden (L Minthon MD); Department of Introduction As a monotherapy, memantine has positive effects on Primary Care, Kalix Vårdcentral, Individuals with Alzheimer’s disease eventually develop global function and cognition in individuals with Kalix, Sweden (S Båtsman MD); severe dementia and as a result become further cognitively moderate-to-severe Alzheimer’s disease9 and on global and Pfizer AB, PO Box 501, Täby, Sweden (A-L Wetterholm, impaired. As their health deteriorates they become less function in severe Alzheimer’s disease.10 Our aim was to C Jansson-Blixt PhD, able to communicate and less mobile, develop apraxia, assess the effect of donepezil on cognition and activities A Haglund BSc) agnosia, and neuropsychiatric symptoms, and need of daily living in patients with severe Alzheimer’s disease Correspondence to: increasing amounts of nursing care. About 20% of patients living in nursing homes ran by trained staff. Prof Bengt Winblad with Alzheimer’s disease have severe dementia.1 The bengt.winblad@ki.se cholinesterase inhibitors donepezil, galantamine, and Methods rivastigmine stabilise or slow down progress in mild-to- Patients moderate disease,2–4 but do not prevent eventual Between October, 2002, and October, 2004, we did a development of severe disease. Some specialists and double-blind, parallel-group, placebo-controlled study in treatment guidelines5 recommend discontinuation of patients living in 50 assisted-care facilities (nursing cholinesterase inhibitors once a patient reaches this stage. homes run by trained staff) in Sweden. Our inclusion Results of studies of donepezil that have included criteria were age 50 years or older, ability to walk alone or patients with severe Alzheimer’s disease are not with help, a mini mental state examination (MMSE)11 consistent, since improvement in some variables (global score of 1–10, and a functional assessment staging (FAST) function and cognition) but not all (behaviour and rating of stage 5 (requires assistance in choosing proper function) were noted in patients living in nursing homes,6 clothing) to 7c (non-ambulatory—unable to walk without whereas there was effective management of cognitive, assistance).12 All patients considered for inclusion had to functional, and behavioural symptoms in those living in have a diagnosis of probable or possible Alzheimer’s the community.7 Co-administration of the N-methyl-D- disease consistent with the Diagnostic and Statistical aspartate receptor antagonist memantine with donepezil Manual of Mental Disorders—Fourth Edition (DSM-IV)13 further slows cognitive and functional deterioration in and the criteria of the National Institute of Neurological patients with moderate-to-severe Alzheimer’s disease.8 and Communicative Disorders and Stroke/Alzheimer’s www.thelancet.com Vol 367 April 1, 2006 1057 Articles Disease and Related Disorders Association (NINCDS- 334 patients assessed ADRDA).14 A CT or MRI scan consistent with Alzheimer’s for eligibility disease (mostly done at the time of diagnosis) was 85 not eligible required. Providing the patient had no other change in 70 did not meet clinical status suggestive of stroke or possible neurological inclusion criteria 2 adverse events disease between the time of the scan and the screening 3 died visit they were allowed to participate. Vital signs and 1 no longer willing laboratory values had to be within their normal range for to participate 9 other age. Our exclusion criteria included the presence of dementias not associated with Alzheimer’s disease, and 249 enrolled and primary psychiatric and neurological disorders. randomised The independent ethics committees of the participating 1 withdrawn after centres approved the study. We obtained written consent randomisation to from the patient (if capable) and in all cases from the placebo but before patients’ next of kin before enrolment. The trial was done treatment because of laboratory in compliance with the Declaration of Helsinki. abnormality Procedures Most participants lived in care units exclusively for patients 128 assigned donepezil 120 assigned placebo with dementia. Each patient had his or her own room in a 33 discontinued 21 discontinued department or unit housing 5–15 individuals. All units 8 died 12 died had a central nurses’ station staffed by professional nurses 20 adverse events 8 adverse events 2 withdrew consent/ 1 withdrew consent/ who developed care plans, dispensed drugs, and oversaw lost to follow-up lost to follow-up care, and by nursing assistants who provided assistance 3 other with activities of daily living. To enable adequate reporting of functional and neuropsychiatric assessments, we 95 completed 6 months' 99 completed 6 months' follow-up follow-up required that nursing assistants had known their patient for at least 12 weeks and that they had spent at least 4 h Figure 1: Trial profile with them on at least 3 days every week. Although some institutions had their own physicians, most were visited on a weekly basis by a family doctor or, in some instances, Donepezil (n=128) Placebo (n=120) a geriatrician. Age (years) 84·5 (6·0) 85·3 (5·9) The randomisation schedule was generated centrally Sex by the Global Clinical Data Services at Pfizer, Groton, Male 27 (21%) 31 (26%) Connecticut, USA. The randomisation was in a one-to- Female 101 (79%) 89 (74%) one ratio, with a block size of four and we provided each Race site with a set of unique numbers. Patients were White 128 (100%) 119 (99%) randomised to donepezil or placebo sequentially, starting Unspecified 0 1 (1%) from the lowest allocation number, according to the Weight (kg) 62·7 (11·3; n=104) 61·5 (12·4; n=100) computer-generated randomisation schedule. Patients Height (cm) 161 (9·3; n=93) 160·9 (9·3; n=95) received a daily dose of oral donepezil 5 mg for the first MMSE screening scores 6·0 (3·0) 6·2 (3·0) 30 days followed by daily donepezil 10 mg (or 5 mg if not FAST stage well tolerated) for the remainder of the 6 months, or 5: Requires assistance in choosing proper clothing 8 (6%) 5 (4%) matching placebo. for the season or occasion Our primary outcome measures were the change from 6a: Difficulty putting clothing on properly without assistance 3 (2%) 8 (7%) baseline to month 6 in the scores for the severe impairment 6b: Unable to bathe properly 12 (9%) 10 (8%) battery (SIB)15,16 and the Modified Alzheimer’s Disease 6c: Inability to handle mechanics of toileting 34 (27%) 22 (18%) Cooperative Study activities of daily living inventory for 6d: Urinary incontinence 18 (14%) 28 (23%) severe Alzheimer’s disease (ADCS-ADL-severe).17,18 The 6e: Faecal incontinence 23 (18%) 16 (13%) SIB is a 40-item questionnaire designed to assess the 7a: Ability to speak limited to about 12 words in an average day 11 (9%) 9 (8%) severity of cognitive dysfunction in advanced Alzheimer’s 7b: Intelligible vocabulary limited to one word in an average day 10 (8%) 8 (7%) disease and is divided into nine domains: memory, 7c: Non-ambulatory (unable to walk without assistance) 9 (7%) 14 (12%) language, orientation, attention, praxis, visuospatial, construction, orientation to name, and social interaction. Data are number (%) or mean (SD). Total scores for the questionnaire range from zero (greatest Table 1: Baseline characteristics impairment) to 100 (no impairment). The modified ADCS- ADL-severe is a 19-item scale used to measure basic and 1058 www.thelancet.com Vol 367 April 1, 2006 Articles complex abilities and validated in patients with moderate- treatment difference in SIB scores over time, according to-severe dementia;18 total scores range from zero to 54, to the results of a previous study of donepezil.7 Since 15% with the lowest score indicating the greatest functional of screened patients would probably not meet our impairment and the highest no impairment. Items inclusion criteria and only 85% of those randomised included basic activities of daily living—eg, eating and would probably complete the trial, we needed to screen bathing—and complex activities of daily living—eg, about 280 patients. operating water taps and switching on lights. Our We did initial analyses of our primary outcome secondary outcome measures were change in scores at measures—the mean of the change from baseline to 6 months compared with screening for the MMSE, month 6 in the SIB and the ADCS-ADL-severe (total baseline for the neuropsychiatric inventory (NPI),19 and scores)—on data obtained from a modified intent-to-treat scores at month 6 for the clinical global impression of population, with last observation carried forward to improvement (CGI-I) scale.20 We ascertained all scores at account for missing data. We defined this population as all baseline, except for MMSE, which was obtained at randomised patients who took at least one dose of screening, 3 months (except for MMSE), and 6 months. medication and who provided a baseline score and at least We assessed vital signs at screening, baseline, and one corresponding post-baseline score. We did secondary months 1, 3, and 6, and adverse events at baseline and analyses on data from the whole intention-to-treat months 1, 3, and 6. Nursing staff also recorded adverse population—ie, all patients who fulfilled the inclusion events daily. We did physical examinations, an ECG, and criteria and who were randomised—and replaced missing laboratory tests, at screening and at month 6. data with the mean of the observed values for the change from baseline to month 6 in the placebo group. We also Statistical analysis did analyses for the completer population, defined as the On the basis of the results of a study of memantine in patients who completed the 6-month treatment period patients with moderate-to-severe Alzheimer’s disease,9 with no provision made for missing data. In a post-hoc we calculated that we needed a sample size of 101 patients sub-item analysis, we analysed each of the nine SIB per treatment group to detect with 90% power an absolute domains and the basic and complex components of ADCS- difference between treatments in ADCS-ADL-severe of ADL-severe separately, comparing change from baseline 3·5 (SD=7·6) with an α level of 0·05. With the same to month 6 for the modified intention-to-treat population. power and significance level, we needed to enrol 86 We did analyses of the secondary outcome measures of patients per group to detect a 7 (SD=14) point absolute the change from screening (MMSE) and baseline (NPI) Baseline (mean, SD) LS mean change from baseline at 6 months (score, SEM)* Completer population Modified intention-to-treat population Intention-to-treat population Donepezil Placebo Donepezil Placebo p Donepezil Placebo p Donepezil Placebo p SIB Score 54·4 (23·8) 56·5 (24·1) 4·0 (1·6) –1·8 (1·5) 0·008 3·4 (1·5) –2·2 (1·5) 0·008 2·6(1·2) –1·9(1·2) 0·01 Number of 109 107 95 98 .. 109 107 .. 128 120 ·· patients ADCS-ADL-severe Score 14·4 (9·1) 14·0 (8·5) –1·1 (0·6) –2·9(0·6) 0·03 –1·4 (0·5) –3·0 (0·5) 0·03 –1·5(0·4) –2·9(0·5) 0·03 Number of 109 107 95 98 .. 109 107 .. 128 120 ·· patients CGI-I Score .. .. 3·3 (1·4) 3·7 (1·2) 0·008 3·4 (1·4) 3·7 (1·2) 0·055 3·5(1·2) 3·8(1·1) 0·01 Number of 111 107 97 99 .. 111 107 .. 128 120 .. patients MMSE Score 5·8 (3·1) 6·3 (3·0) 1·5 (0·4) 0·1(0·4) 0·009 1·5 (0·4) 0·1 (0·4) 0·009 1·1(0·3) 0·1(0·3) 0·01 Number of 95 98 95 98 .. 95 98 .. 120 120 .. patients NPI Score 19·0 (15·2) 19·6 (15·8) –4·1 (1·4) –2·3 (1·3) 0·33 –3·2 (1·3) –1·7 (1·4) 0·43 –3·8(1·1) –2·1 (1·1) 0·26 Number of 109 107 95 97 .. 109 107 .. 128 120 .. patients *Exceptions for CGI-I, where scores at month 6 provided, and MMSE, where LS mean changes from screening provided. Test of treatment effect based on ANCOVA model, with baseline value as covariate. Table 2: Effect of treatment on primary and secondary outcome measures www.thelancet.com Vol 367 April 1, 2006 1059 Articles SIB tests were two-sided and we judged a p value of 0·05 or 7 p=0·003 less significant. 95% CIs are presented for the estimates Donepezil Placebo p=0·008 derived from data from the modified intention-to-treat 6 p=0·008 population and the intention-to-treat population. 5 LS mean change from baseline (SE) For safety variables, we present descriptive statistics for 4 all patients who were randomised and took at least one 3 Clinical dose of study medication. We recorded all treatment- improvement 2 emergent adverse events, coding them according to a 1 modified COSTART dictionary.21 Rates for adverse events, 0 laboratory abnormalities, and changes in ECGs are –1 summarised. All statistical analyses were done with SAS (version 8.2). –2 Clinical decline –3 Role of the funding source –4 0 Month 3 Month 6 Month 6 Study design and planning, data collection, data analysis, completer completer modified data interpretation, and writing of the report were done population population intention-to- in conjunction with the study sponsor. The study sponsor treat population Donepezil (n=109) 109 95 (109) provided the study drugs and funding for study Placebo (n=107) 107 98 (107) management. The corresponding author had full access to all the data in the study and had final responsibility for ADCS–ADL-severe Clinical the decision to submit for publication. 1 Donepezil improvement Placebo Results p=0·09 p=0·03 Of the 334 patients screened, we randomised and treated LS mean change from baseline (SE) 0 p=0·03 248 (figure 1). There were no notable differences between the groups with respect to their demographic or –1 Clinical psychometric characteristics at baseline (table 1). decline 95 patients assigned donepezil and 99 controls completed the study. The median duration of treatment with –2 donepezil was 176 days (range 2–231) and with placebo 180 days (5–218). Mean daily doses of donepezil and –3 placebo for the safety population were 8·2 mg (SD 1·5) and 8·4 mg (1·2), respectively. 91% (n=86) of donepezil- –4 treated patients and 94% (n=93) of controls who 0 Month 3 Month 6 Month 6 completed the study took the 10 mg dose. completer completer modified More than 80% of patients had FAST scores of 6c or population population intention-to- treat population higher (table 1). At baseline, in donepezil-treated and Donepezil (n=109) 109 95 (109) placebo-treated patients, hypertension was present in Placebo (n=107) 107 98 (107) 29% (n=37) and 25% (n=30), heart disease in 29% (n=37) and 23% (n=28), and psychiatric symptoms in 68% (n=87) Figure 2: Effect of treatment on SIB and ADCS-ADL-severe scores and 75% (n=90), respectively. All donepezil and most (99%, n=247) placebo patients took concomitant to month 6 (total scores) on the modified intention-to- medications during the study. Most commonly used treat population, the intention-to-treat population, and classes of drugs were analgesics, laxatives, hypnotics, the completer population. We analysed primary and sedatives and anxiolytics, diuretics, drugs used to treat secondary outcome measures with the general linear anaemia, antidepressants, drugs to treat rheumatic model, which included treatment and baseline data as diseases and gout, antibacterial agents, and antipsychotic covariates. Treatment was included as a fixed effect. drugs. More than 80% of patients were taking psychoactive Furthermore, as a sensitivity analysis, we included the medications, with a breakdown by class as follows: centre as a covariate in the model (centres with less than hypnotics, sedatives, and anxiolytics, 61% (donepezil, five patients in each treatment group were pooled). We n=78) versus 58% (placebo, n=70); antidepressants, 52% analysed the CGI-I scores for the modified intention-to- (n=67) versus 51% (n=61); antipsychotics, 38% (n=48) treat population, the intention-to-treat population, and versus 42% (n=50). the completer population, using the Cochran-Mantel- At 6 months, according to last observation carried Haenszel χ² test stratified by centre. forward analyses done in the modified intention-to-treat We used paired t tests to compare pretreatment with population, patients assigned donepezil had significantly post-treatment data in each treatment group. All statistical better mean change from baseline scores than controls 1060 www.thelancet.com Vol 367 April 1, 2006 Articles on both SIB (least squares [LS] mean difference 5·7, p<0·05 95% CI 1·5–9·8; p=0·008) and ADCS-ADL-severe (1·7, 0·2–3·2; p=0·03). Indeed, donepezil-treated patients 10 Donepezil (n=109) showed a mean improvement in SIB, whereas those 8 Placebo (n=107) Clinical receiving placebo showed a mean decline (table 2). The improvement 6 LS mean change from baseline donepezil group showed less of a decline than the placebo domain score at month 6 4 group in ADCS-ADL-severe (table 2). Figure 2 shows the results for the modified intention-to-treat population and 2 for the completer population. The outcome analyses in 0 which we replaced missing values by the mean of the –2 observed values for the change from baseline to month 6 –4 in the placebo group revealed similar results as for the –6 primary modified intention-to-treat population (table 2). Clinical We noted significant treatment differences for the –8 decline intention-to-treat population: SIB (LS mean difference –10 n y n ge n is l n e tia or am io tio io io ax ua 4·5, 1·1–7·9; p=0·01) and ADCS-ADL-severe (1·4, pa em ct nt ct Pr ta gn ng ra tru te os ien M te tin At La su ns 0·1–2·7; p=0·03). l in Or Vi ien Co cia Or So Analysis of the individual SIB domains at 6 months for the modified intention-to-treat population showed Figure 3: Effect of treatment on individual SIB domain scores (modified intention-to-treat population) donepezil to be more effective than placebo in all items, with improvement above baseline in eight domains, Basic domains compared with only two for placebo (figure 3). At 0·5 Donepezil (n=109) 6 months, for the same population, donepezil positively 0·4 Placebo (n=107) p<0·05 Clinical improvement affected five of six basic ADCS-ADL-severe items and 11 0·3 LS mean change from baseline of 13 complex ADCS-ADL-severe items, resulting in domain score at month 6 0·2 improvement in four items compared with one item for placebo (figure 4). 0·1 Two of the three secondary outcome measures—the 0 CGI-I scores and the mean change from screening scores –0·1 on the MMSE at 6 months’ follow up—favoured donepezil –0·2 treatment over placebo (table 2). For the CGI-I score, the –0·3 difference between treatment groups was almost –0·4 Clinical decline significant in the modified intention-to-treat population –0·5 (p=0·055) and significant when only the data for the g g n g g d tin in in in se tio completer population were analysed (p=0·008; figure 5). alk th m es Ea nc oo Ba dr W fu Gr ng r For the MMSE, donepezil-treated patients had a greater de tti lad Ge l/b mean improvement than controls, with LS mean changes we Bo of 1·5 and 0·1, respectively, for the modified intention-to- treat population (LS mean difference 1·4, 95% CI 0·4–2·4; Complex domains p=0·009). There was no significant difference between 0·5 Donepezil (n=109) treatment groups on the NPI for the modified intention- 0·4 Placebo (n=107) p<0·05 Clinical improvement to-treat population (1·5, –5·3 to –2·2; p=0·43). 0·3 LS mean change from baseline The overall incidence of adverse events was comparable domain score at month 6 0·2 between groups (donepezil 82% [n=105] vs placebo 76% 0·1 [n=91]), with most being transient and mild or moderate in severity. Of the most common adverse events 0 (occurring in ≥5% of patients in either group), only –0·1 diarrhoea and hallucinations were reported at more than –0·2 twice the rate in donepezil-treated patients compared –0·3 with controls (table 3). A similar number of deaths –0·4 Clinical decline occurred during and within 30 days after the study in the –0·5 donepezil (14% [n=18]) and placebo (16% [n=19]) groups. e n n s s ge ng sh nd e er on r s s e he ng ht ht on m io tio at at i ra ou b lig lig ho s s i We did not consider any of the deaths treatment related. ph nw w sa ub Ob ong i Fin r di ve lev ar off off er m ele be fr ea Ru te el nv ro eo rn et rn rn in Cl db The proportion of patients who had a serious adverse ch tti yf Co Tu Tu ta Tu Us os at Ge wa sp W ea Di event (including one with an outcome of death) during on Al the study or within the 30-day study lag period did not differ between groups (24% [n=31] vs 26% [n=31], Figure 4: Effect of treatment on basic and complex ADCS-ADL-severe domain scores www.thelancet.com Vol 367 April 1, 2006 1061 Articles CGI-I Completer population Modified intention-to-treat population 50 40 Donepezil (n=111) Donepezil (n=97) Proportion of patients on CGI-I (%) Proportion of patients on CGI-I (%) Placebo (n=99) Overall Placebo (n=107) Overall 40 p=0·008 p=0·055 30 30 20 20 10 10 0 0 ed ed ed ge se se se ed ed ed ge se se se or or or or or or an ov ov ov an ov ov ov yw hw hw yw hw hw pr pr ch pr pr pr pr ch m m m im m m all No uc uc all No uc uc hi hi yi hi yi im M m im M m h all uc uc all uc uc in ry in ry im ym M im m M M Ve M Ve in in ry r M Ve M Ve ac us ac us ac us ac us pl rs pl rs pl rs pl rs o o o o % l ve % l ve % l ve % l ve eb eb eb eb 36 pezi 25 ezi 38 pezi 25 ezi p p ne ne ne ne do do do do % % % % 59 18 53 21 MMSE NPI p=0·009 3 Donepezil 6 Donepezil Placebo Placebo p=0·009 p=0·009 LS mean change from baseline (SE) LS mean change from baseline (SE) 2 5 Clinical Clinical 4 1 improvement improvement 3 0 2 –1 Clinical 1 Clinical decline decline –2 0 –3 –1 0 Month 6 Month 6 0 Month 3 Month 6 Month 6 completer modified completer completer modified population intention-to-treat population population intention-to- population treat population Donepezil (n=95) 95 95 Donepezil (n=109) 108 95 (109) Placebo (n=98) 98 98 Placebo (n=107) 107 97 (107) Figure 5: Effect of treatment on secondary outcomes variables respectively). More patients treated with donepezil than therapy for 3 months before study entry and for the most controls discontinued their treatment, however, because part had a limited exposure to such agents during the of adverse reactions (16% [n=20] vs 7% [n=8]). course of their disease. The study was not designed to We noted no great changes in the results of laboratory further clarify the issue of discontinuation of therapy tests, ECGs, physical examinations, or vital signs over once the patient reaches this juncture. time. Similar to results obtained in patients with moderate- to-severe Alzheimer’s disease living in the community,7 Discussion the advantages afforded by 6 months of treatment with Our findings indicate that donepezil can improve donepezil in cognition, activities of daily living, and cognition and preserves function in patients with severe global function included improvements above baseline Alzheimer’s disease. The data presented lend support to or less decline compared with placebo. The improvements the neurobiological premise that cholinergic deficits in in cognition seem to have a positive effect on the the brain of people with severe Alzheimer’s disease can functioning of the patients, potentially indicating a direct be, at least in part, alleviated by cholinesterase inhibitors.22 correlation between these two domains. The pronounced Our patients had not received cholinergic inhibitor improvement in SIB scores in patients treated with 1062 www.thelancet.com Vol 367 April 1, 2006 Articles patients to have better outcomes on most items. As well Donepezil (n=128) Placebo (n=120) as improving wellbeing of patients, benefits in functional Urinary tract infection 22 (17%) 19 (16%) capacity could translate to decreased workload and less Accidental fall 17 (13%) 15 (13%) stress for nursing staff in assisted-care facilities and for Anxiety 8 (6%) 10 (8%) other caregivers, including relatives. Indeed, donepezil Accidental injury 7 (6%) 6 (5%) has been shown to reduce burden in caregivers of patients Gastroenteritis 8 (6%) 12 (10%) with moderate-to-severe Alzheimer’s disease.24 Diarrhoea 12 (9%)* 3 (3%) Comparisons between our study and those of other Pneumonia 12 (9%) 7 (6%) treatments for dementia are difficult to make. The only Cystitis 8 (6%) 5 (4%) other study of treatment of severe dementia in patients Nausea 8 (6%) 5 (4%) living in nursing homes was of a relatively short course of Asthenia 4 (3%) 7 (6%) memantine10 and only half those enrolled had Alzheimer’s Accidental bone fracture 7 (6%) 4 (3%) disease. Nevertheless, similar results on the CGI-I were Constipation 5 (4%) 6 (5%) obtained.10 In a study of memantine in patients with Hallucinations 8 (6%) †‡ 1 (1%)§ moderate-to-severe Alzheimer’s disease living in the Total 311 220 community,9 treatment duration was more similar to that *Possibly treatment-related in eight (6%) patients. †Possibly treatment-related in four in our study. In that study, as in ours, significant treatment (3%) patients. ‡Present before start of study in three patients. §Present before start of differences at final follow-up were noted in favour of study in one patient. active medication compared with placebo on the SIB and Table 3: Adverse events (all causalities) reported in at least 5% of ADCS-ADL-severe. However, whereas both medications patients in either treatment group slowed functional decline, cognitive improvements above baseline were noted only for donepezil. donepezil might have been driven by an improvement in To calculate the sample number needed to sufficiently delirium or confused states in a subset of patients or by power our study, we set a clinical significance, based on direct action of donepezil against the anticholinergic or studies in a population of patients with moderate-to- sedative effects of concomitant medications. Analyses of severe Alzheimer’s disease,7,9 at a treatment difference of subsets of patients taking different classes of medication 7 points on the SIB and 3·5 points on the ADCS-ADL- need to be done to explore these possibilities. severe. Although the point estimates of the treatment As in the study by Reisberg and colleagues9 of differences at 6 months were smaller than specified a memantine, we noted little effect of donepezil compared priori and than those noted in the memantine study with placebo on the NPI. This finding also concurs with (SIB 6·1 points; ADCS-ADL-severe 2·1 points),9 the range that of a previous study6 of donepezil in patients with of values for SIB was within that of clinical significance. mild-to-severe Alzheimer’s disease living in nursing The high baseline scores for the SIB (by 20%) and the homes, but contrasts with significant differences noted ADCS-ADL-severe (by 75%) in the memantine trial9 in favour of donepezil in a study based in the community.7 compared with ours could have affected the possible As such, there might be an inherent difference between range of the changes in a different way to those noted studying behavioural aspects of Alzheimer’s disease in here because of differential sensitivities in different parts patients residing in different settings and a differential of the scale. Before we did our study, it was difficult to sensitivity of the NPI in these settings. Alternatively, use define clinically relevant effect size in a population with of concomitant psychoactive medication might have severe Alzheimer’s disease because of the limited data masked a behavioural response to donepezil in some available. Moreover, treatment effects of cholinesterase patients. Sub-item and responder analyses need to be inhibitor therapies are not large.25 Small numerical done to fully ascertain the effects of donepezil on changes on scales used to measure symptomatic changes behaviour. in trials might nevertheless be clinically meaningful in Sustained use of cholinesterase inhibitors is not practice. It is noteworthy that this elderly patient associated with any survival advantage.23 Thus, if population, with multiple comorbidities, is a vulnerable treatment can help patients in the late phase of dementia, one. As such, changes to their condition, mediated by without necessarily increasing the length of time they factors other than Alzheimer’s disease—eg, infection— have severe Alzheimer’s disease, then this is a treatment might result in a high level of variation in response. option that should be available. Results of sub-item Over the past few years, a study period of around analysis of the SIB showed nearly all aspects of cognition 6 months seems to have become the optimum duration measured to be improved in patients treated with for assessing the efficacy of dementia medications; its donepezil. An increase in the ability to communicate is use here enables comparison with other studies of especially important, since it facilitates caregiving Alzheimer’s disease. A shorter study period of 3 months through improved interaction and helps to maintain might not be sufficient to observe effects. Moreover, a contact with family members. More in-depth analysis of high attrition rate, a common problem in clinical trials basic activities of daily living showed donepezil-treated that enrol elderly and vulnerable populations, is www.thelancet.com Vol 367 April 1, 2006 1063 Articles exacerbated when studies continue over a long period Lars Sköldstam, Neurologmottagningen, Visby; David Karlsson, (12 months or more), compromising the validity of the Geriatriska Rehab-kliniken, Värnamo; Birger Ossiansson, Vårdcentralen Birka, Växjö; Göran Rehn, Smedbyhemmet, Akersberga; end results. Indeed in this 6-month trial, the overall Rachel Gille, Årsta Vårdcentral, Årsta; Per Åkesson, Vårdcentralen, Sunne; withdrawal rate was 22%. Although different imputation Viveka Norlund-Elmroth Distriktsläkarmott, Östersund; Lars-Bertil Olsson, methods for handling missing data revealed similar Vårdcentralen Kristina, Kristinehamn; Benny Lorentzon, Vårdcentralen results, this high drop-out rate should be considered Källstorp, Trollhättan; Inger Grönlund-Brown, Vårdcentralen Sjuntorp, Sjuntorp; Hans Högström, Tyresöhälsan Husläkare AB, Tyresö; during interpretation of the data. Martin Frykholm, Åsö Vårdcentral, Stockholm; Kent Fredriksson, As in studies of mild-to-moderate26–29 and moderate-to- Särö Vårdcentral/Särö Hemsjukvård, Särö; Tom Roffey, Ågårdsskogens severe Alzheimer’s disease,7 donepezil was well tolerated, Vårdcentral, Lidköping; Lars Paulsson, Västra Eketorps Läkarmottagning, with side-effects typical of cholinesterase inhibitor Gullspång; Lars-Olof Petersson, Lovåsens Vårdcentral, Katrineholm; Bengt Kvarnlind, Storviks Hälsocentral, Sandviken; Holger Källqvist, therapy—eg, diarrhoea and hallucinations. Hallucinations Vårdcentralen Nygård, Bengtsfors; Anders Wimo, Bergsjö Hälsocentral, were present, however, before the start of the study in Bergsjö; Carl-Johan Westborg, Björknäs Vårdcentral, Boden; three of the eight donepezil-treated patients and in one Jerry Dahlberg, Sollebrunn Vårdcentral, Sollebrunn; Pirkko Olsson, placebo patient, and might be a manifestation of the Vårdcentralen, Tullinge. disease rather than a side-effect of treatment. As expected, Acknowledgments more patients taking donepezil than placebo left the This study was funded by Pfizer Pharmaceuticals, Sollentuna, Sweden. study. References 1 Aguero-Torres H, Fratiglioni L, Winblad B. Natural history of Overall, our data suggest that donepezil is an effective Alzheimer’s disease and other dementias: review of the literature in and well tolerated treatment even when initiated in the light of the findings from the Kungsholmen Project. patients with severe Alzheimer’s disease Int J Geriatr Psychiatry 1998; 13: 755–66. 2 Wilcock GK, Lilienfeld S, Gaens E. Efficacy and safety of Contributors galantamine in patients with mild to moderate Alzheimer’s disease: B Winblad conceived the study, secured funding from Pfizer, and, multicentre randomised controlled trial. BMJ 2000; 321: 1445–49. together with A Haglund, designed the study protocol. A Haglund and 3 Whitehead A, Perdomo C, Pratt RD, Birks J, Wilcock GK, Evans JG. A-L Wetterholm helped find study centres, oversaw good clinical Donepezil for the symptomatic treatment of patients with mild to practice, monitored study sites, and, in conjunction with C Jansson-Blixt, moderate Alzheimer’s disease: a meta-analysis of individual patient developed clinical report forms. A-L Wetterholm also ensured staff at data from randomised controlled trials. study centres were adequately trained. C Jansson Blixt was involved in Int J Geriatr Psychiatry 2004; 19: 624–33. the verification of randomisation. L Kilander and S Båtsman helped 4 Ritchie CW, Ames D, Clayton T, Lai R. Metaanalysis of randomized enrol patients and, together with B Winblad, S Eriksson, and trials of the efficacy and safety of donepezil, galantamine, and C Jansson-Blixt, were involved in data analysis. B Winblad, L Kilander, rivastigmine for the treatment of Alzheimer disease. S Eriksson, S Båtsman, L Minthon, C Jansson-Blixt, and A Haglund Am J Geriatr Psychiatry 2004; 12: 358–69. were involved in writing of the report. 5 National Institute for Health and Clinical Excellence. Appraisal consultation document: donepezil, galantamine, rivastigmine Conflict of interest statement (review) and memantine for the treatment of Alzheimer’s disease. B Winblad and S Eriksson have taken part in advisory board meetings of http://www.nice.org.uk/page.aspx?o=288878 (accessed March 3, 2006). drug companies producing drugs to treat dementia. L Kilander has 6 Tariot PN, Cummings JL, Katz IR, et al. A randomized, double- received honoraria from Pfizer to speak at meetings and is on their blind, placebo-controlled study of the efficacy and safety of advisory board. S Båtsman has taken part in advisory board meetings of donepezil in patients with Alzheimer’s disease in the nursing home Pfizer and Lundbeck and has received honoraria to speak at meetings setting. J Am Geriatr Soc 2001; 49: 1590–99. from Pfizer, Novartis, and Lundbeck. L Minthon has arranged lectures 7 Feldman H, Gauthier S, Hecker J, Vellas B, Subbiah P, Whalen E. paid for by Janssen Cilag and Pfizer, is on the advisory board of Pfizer A 24-week, randomized, double-blind study of donepezil in and Lundbeck and for the Severe Alzheimer Dementia Study, and has moderate to severe Alzheimer’s disease. Neurology 2001; 57: 613–20. received funding from Pfizer to arrange a national conference 8 Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, (Specialistforum Demens). C Jansson-Blixt and A Haglund are, and Gergel I. Memantine treatment in patients with moderate to severe A-L Wetterholm was, employed by Pfizer. Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA 2004; 291: 317–24. Severe Alzheimer’s Disease Study Group 9 Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. 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