Winblad_subbed.qxp 6/8/09 10:12 Page 54
Pharmacotherapy
Figure 1: Swedish Nursing Home study
13
Figure 2: Multinational Study
14
A
A
7
p=0.03
p=0.08 10
6
p=0.08
5
8
4
Clinical
6 Clinical
3
improvement 4
improvement
2
1
2
0 0
Baseline
-1
-2
LS mean change from
baseline ± SE on the SIB
-2
-4 Clinical
-3
Clinical
-4
decline -6
decline
0 Month 3 Month 6 Month 6
LS mean change from baseline
completer completer modified ITT
domain score at week 24 (LOCF)
-8
population population population
-10
with LOCF
axis
Donepezil
Social
Pr (n=166)
action Memory
Donepezil 109 95 (109)
Placebo 107 98 (107)
inter
Orientation
LanguageAttention
Visuospatial
Construction
Placebo
(n=166)
Orientating name
B
1
p=0.09
B
0
50
48.10
p=0.03
Clinical
p=0.03
improvement
45
-1 *
)
%
40
38.30
*
-2
35
34.00
-3
Clinical *
decline
P
atients (
29.20
30 27.80
± SE on the ADSC-ADL-sev
LS mean change from baseline
-4
0 Month 3 Month 6 Month 6
25 22.70
completer completer modified ITT
population population population
20
with LOCF
Improved No change Worsened
Donepezil
(n=166)
Donepezil n=109 109 95 (109)
Collapsed category
ITT-LOCF
Placebo
Placebo n=107 107 98 (107) *p=0.0473 (n=166)
Effect of donepezil treatment on (A) Severe Impairment Battery (SIB) and (B) Alzheimer’s Effect of donepezil treatment on (A) Severe Impairment Battery (SIB) individual domain
Disease Co-operative Study—Activities of Daily Living modified for severe Alzheimer’s disease analysis scores and (B) Clinician’s Interview-Based Impression of Change-plus caregiver
(ADCS-ADL-sev) scores. LS = least squares; ITT = intent to treat; LOCF = last observation interview (CIBIC-plus) scores (three-category collapsed analysis). LS = least squares;
carried forward. ITT = intent to treat; LOCF = last observation carried forward.
donepezil in patients with severe AD. The Swedish Nursing Home The third study was similar in design to the multinational severe
Severe AD study
13
was the first large-scale randomised controlled trial trial but included both 5 and 10mg/day doses of donepezil, and was
of a ChEI in a patient population exclusively with severe AD. The performed in a Japanese patient population.
15
Enrolled patients had
trial lasted for six months and studied patients with severe AD (MMSE MMSE scores between 1 and 12 and FAST scores ≥6. Results
score 1–10) who were living in assisted-care nursing homes in from this trial also echoed the multinational severe study;
Sweden. Patients treated with donepezil 10mg/day showed significant patients receiving donepezil 10mg/day had significantly better
improvements in cognition (Severe Impairment Battery [SIB]) and cognitive (SIB) and global function (seven-category and collapsed
less functional decline (Alzheimer’s Disease Co-operative three-category analysis of the CIBIC-plus) outcomes compared with
Study-Activities of Daily Living modified for severe AD [ADCS-ADL-sev]) those receiving placebo (see Figure 3). SIB scores were also
compared with placebo patients (see Figure 1).
13
Although there was significantly improved compared with placebo in patients receiving
no significant difference between treatment groups on the measure of donepezil 5mg/day, but there was no statistical difference between
behaviour, the Neuropsychiatric Inventory (NPI), there was a the two groups in the distribution of CIBIC-plus scores using
numerically greater improvement with donepezil. either the seven-category or collapsed three-category analysis.
In addition, a significant dose–response relationship was
The second trial was a 24-week multinational, randomised, demonstrated on both the SIB and the CIBIC-plus. No significant
double-blind, placebo-controlled study of donepezil treatment in differences between treatment groups were seen for measures of
patients with severe AD (MMSE scores 1–12 and Functional behaviour (Behavioural Pathology in Alzheimer’s Disease Rating
Assessment Staging [FAST] scores ≥6).
14
The cognitive (SIB and MMSE) Scale) or function (ADCS-ADL-sev).
and global function (collapsed three-category analysis of the
Clinician’s Interview-Based Impression of Change-plus care-giver The fourth study of donepezil in patients with severe AD was part
interview [CIBIC-plus]) results of patients receiving donepezil of a larger 24-week randomised, placebo-controlled study looking
10mg/day were significantly better than those receiving placebo at patients with MSAD that recruited patients in Canada, Australia
(see Figure 2). Changes in function (ADCS-ADL-sev) were not and France.
17
Those with more severe disease (standardised MMSE
significantly different between treatment groups and, as in the [sMMSE] 5–12) formed a subgroup that was analysed separately.
16
Swedish study, both donepezil and placebo groups showed a trend After 24 weeks of treatment, patients receiving donepezil had
towards an improvement in NPI scores from baseline, but differences significantly better results in terms of cognition (sMMSE and SIB),
were not significant between the groups. global function (CIBIC-plus), function (Disability Assessment for
54 EUROPEAN PSYCHIATRIC REVIEW