Clinical Trial Data
The effectiveness of ARICEPT® as a treatment for Alzheimer's
Disease is demonstrated by the results of two randomized, double-blind, placebo-controlled
clinical investigations in patients with mild to moderate Alzheimer's Disease
and in patients with severe Alzheimer's Disease.
Mild-Moderate Alzheimer's Disease
The effectiveness of ARICEPT® as a treatment for mild
to moderate Alzheimer's Disease is demonstrated by the results of two randomized,
double-blind, placebo-controlled clinical investigations in patients with Alzheimer's
Disease (diagnosed by NINCDS and DSM III-R criteria, Mini-Mental State Examination
≥ 10 and ≤ 26 and Clinical Dementia Rating of 1 or 2). The mean age of patients
participating in ARICEPT® trials was 73 years with a range
of 50 to 94. Approximately 62% of patients were women and 38% were men. The racial
distribution was white 95%, black 3% and other races 2%.
Study Outcome Measures: In each study, the effectiveness of treatment
with ARICEPT® was evaluated using a dual outcome assessment
strategy.
The ability of ARICEPT® to improve cognitive performance
was assessed with the cognitive subscale of the Alzheimer's Disease Assessment
Scale (ADAS-cog), a multiitem instrument that has been extensively validated in
longitudinal cohorts of Alzheimer's Disease patients. The ADAS-cog examines
selected aspects of cognitive performance including elements of memory, orientation,
attention, reasoning, language and praxis. The ADAS-cog scoring range is from 0
to 70, with higher scores indicating greater cognitive impairment. Elderly normal
adults may score as low as 0 or 1, but it is not unusual for non-demented adults
to score slightly higher.
The patients recruited as participants in each study had mean scores on the Alzheimer's
Disease Assessment Scale (ADAS-cog) of approximately 26 units, with a range from
4 to 61. Experience gained in longitudinal studies of ambulatory patients with mild
to moderate Alzheimer's Disease suggest that they gain 6 to 12 units a year
on the ADAS-cog. However, lesser degrees of change are seen in patients with very
mild or very advanced disease because the ADAS-cog is not uniformly sensitive to
change over the course of the disease. The annualized rate of decline in the placebo
patients participating in ARICEPT® trials was approximately
2 to 4 units per year.
The ability of ARICEPT® to produce an overall clinical
effect was assessed using a Clinician's Interview Based Impression of Change
that required the use of caregiver information, the CIBIC plus. The CIBIC plus is
not a single instrument and is not a standardized instrument like the ADAS-cog.
Clinical trials for investigational drugs have used a variety of CIBIC formats,
each different in terms of depth and structure.
As such, results from a CIBIC plus reflect clinical experience from the trial or
trials in which it was used and cannot be compared directly with the results of
CIBIC plus evaluations from other clinical trials. The CIBIC plus used in ARICEPT®
trials was a semi-structured instrument that was intended to examine four major
areas of patient function: General, Cognitive, Behavioral and Activities of Daily
Living. It represents the assessment of a skilled clinician based upon his/her observations
at an interview with the patient, in combination with information supplied by a
caregiver familiar with the behavior of the patient over the interval rated. The
CIBIC plus is scored as a seven point categorical rating, ranging from a score of
1, indicating "markedly improved," to a score of 4, indicating "no
change" to a score of 7, indicating "markedly worse." The CIBIC plus
has not been systematically compared directly to assessments not using information
from caregivers (CIBIC) or other global methods.
Thirty-Week Study
In a study of 30 weeks' duration, 473 patients were randomized to receive single
daily doses of placebo, 5 mg/day or 10 mg/day of ARICEPT®.
The 30-week study was divided into a 24-week double-blind active treatment phase
followed by a 6-week single-blind placebo washout period. The study was designed
to compare
5 mg/day or 10 mg/day fixed doses of ARICEPT® to placebo.
However, to reduce the likelihood of cholinergic effects, the 10 mg/day treatment
was started following an initial 7-day treatment with 5 mg/day doses.
Effects on the ADAS-cog: Figure 1 illustrates the time course for
the change from baseline in ADAS-cog scores for all three dose groups over the 30
weeks of the study. After 24 weeks of treatment, the mean differences in the ADAS-cog
change scores for ARICEPT®-treated patients compared to
the patients on placebo were 2.8 and 3.1 units for the 5 mg/day and 10 mg/day treatments,
respectively. These differences were statistically significant. While the treatment
effect size may appear to be slightly greater for the 10 mg/day treatment, there
was no statistically significant difference between the two active treatments.
Following 6 weeks of placebo washout, scores on the ADAS-cog for both the ARICEPT®
treatment groups were indistinguishable from those patients who had received only
placebo for 30 weeks. This suggests that the beneficial effects of ARICEPT®
abate over 6 weeks following discontinuation of treatment and do not represent a
change in the underlying disease. There was no evidence of a rebound effect 6 weeks
after abrupt discontinuation of therapy.
Figure 1. Time-course of the Change from Baseline in ADAS-cog Score for Patients
Completing 24 Weeks of Treatment.
Figure 2 illustrates the cumulative percentages of patients from each of the three
treatment groups who had attained the measure of improvement in ADAS-cog score shown
on the X axis. Three change scores, (7-point and 4-point reductions from baseline
or no change in score) have been identified for illustrative purposes and the percent
of patients in each group achieving that result is shown in the inset table.
The curves demonstrate that both patients assigned to placebo and ARICEPT®
have a wide range of responses, but that the active treatment groups are more likely
to show the greater improvements. A curve for an effective treatment would be shifted
to the left of the curve for placebo, while an ineffective or deleterious treatment
would be superimposed upon or shifted to the right of the curve for placebo, respectively.
Figure 2. Cumulative Percentage of Patients Completing 24 Weeks of Double-blind Treatment
with Specified Changes from Baseline ADAS-cog Scores.
Effects on the CIBIC plus: Figure 3 is a histogram of the frequency
distribution of CIBIC plus scores attained by patients assigned to each of the three
treatment groups who completed 24 weeks of treatment. The mean drug-placebo differences
for these groups of patients were 0.35 units and 0.39 units for 5 mg/day and 10
mg/day of ARICEPT®, respectively. These differences were
statistically significant. There was no statistically significant difference between
the two active treatments.
Figure 3. Frequency Distribution of CIBIC plus Scores at Week 24.
Fifteen-Week Study
In a study of 15 weeks' duration, patients were randomized to receive single
daily doses of placebo or either 5 mg/day or 10 mg/day of ARICEPT®
for 12 weeks, followed by a 3-week placebo washout period. As in the 30-week study,
to avoid acute cholinergic effects, the 10 mg/day treatment followed an initial
7-day treatment with 5 mg/day doses.
Effects on the ADAS-Cog: Figure 4 illustrates the time course of the
change from baseline in ADAS-cog scores for all three dose groups over the 15 weeks
of the study. After 12 weeks of treatment, the differences in mean ADAS-cog change
scores for the ARICEPT® treated patients compared to the
patients on placebo were 2.7 and 3.0 units each, for the 5 and 10 mg/day ARICEPT®
treatment groups respectively. These differences were statistically significant.
The effect size for the 10 mg/day group may appear to be slightly larger than that
for 5 mg/day. However, the differences between active treatments were not statistically
significant.
Figure 4. Time-course of the Change from Baseline in ADAS-cog Score for Patients
Completing the 15-week Study.
Following 3 weeks of placebo washout, scores on the ADAS-cog for both the ARICEPT®
treatment groups increased, indicating that discontinuation of ARICEPT®
resulted in a loss of its treatment effect. The duration of this placebo washout
period was not sufficient to characterize the rate of loss of the treatment effect,
but, the 30-week study (see above) demonstrated that treatment effects associated
with the use of ARICEPT® abate within 6 weeks of treatment
discontinuation.
Figure 5 illustrates the cumulative percentages of patients from each of the three
treatment groups who attained the measure of improvement in ADAS-cog score shown
on the X axis. The same three change scores, (7-point and 4-point reductions from
baseline or no change in score) as selected for the 30-week study have been used
for this illustration. The percentages of patients achieving those results are shown
in the inset table.
As observed in the 30-week study, the curves demonstrate that patients assigned
to either placebo or to ARICEPT® have a wide range of
responses, but that the ARICEPT®-treated patients are
more likely to show the greater improvements in cognitive performance.
Figure 5. Cumulative Percentage of Patients with Specified Changes from Baseline
ADAS-cog Scores.
Effects on the CIBIC plus: Figure 6 is a histogram of the frequency
distribution of CIBIC plus scores attained by patients assigned to each of the three
treatment groups who completed 12 weeks of treatment. The differences in mean scores
for ARICEPT® treated patients compared to the patients
on placebo at Week 12 were 0.36 and 0.38 units for the 5 mg/day and 10 mg/day treatment
groups, respectively. These differences were statistically significant.
Figure 6. Frequency Distribution of CIBIC plus Scores at Week 12.
In both studies, patient age, sex and race were not found to predict the clinical
outcome of ARICEPT® treatment.
Severe Alzheimer's Disease
Swedish 24-Week Study
The effectiveness of ARICEPT® as a treatment for severe
Alzheimer's Disease is demonstrated by the results of a randomized, double-blind,
placebo-controlled clinical study conducted in Sweden (24-Week Study) in patients
with probable or possible Alzheimer's Disease diagnosed by NINCDS-ADRDA and
DSM-IV criteria, MMSE; range of 1-10. Two hundred and forty eight (248) patients
with severe Alzheimer's disease were randomized to ARICEPT®or
placebo. For patients randomized to ARICEPT, treatment was initiated at 5 mg once
daily for 28-days and then increased to 10 mg once daily. At the end of the 24-week
treatment period, 90.5% of the ARICEPT® -treated patients
were receiving the 10 mg dose. The mean age of patients was 84.9 years with a range
of 59 to 99. Approximately 77% of patients were women and 23% were men. Almost all
patients were Caucasian. Probable AD was diagnosed in the majority of the patients
(83.6% of ARICEPT-treated patients and 84.2% of placebo-treated patients).
Study Outcome Measures: The effectiveness of treatment with ARICEPT®
was determined using a dual outcome assessment strategy that evaluated cognitive
function using an instrument designed for more impaired patients and overall function
through caregiver-rated assessment. This study showed that patients on ARICEPT®
experienced significant improvement on both measures compared to placebo.
The ability of ARICEPT® to improve cognitive performance
was assessed with the Severe Impairment Battery (SIB). The SIB, a multi-item instrument,
has been validated for the evaluation of cognitive function in patients with moderate
to severe dementia. The SIB evaluates selective aspects of cognitive performance,
including elements of memory, language, orientation, attention, praxis, visuospatial
ability, construction, and social interaction. The SIB scoring range is from 0 to
100, with lower scores indicating greater cognitive impairment.
Daily function was assessed using the Modified Alzheimer's Disease Cooperative
Study Activities of Daily Living Inventory for Severe Alzheimer's Disease (ADCS-ADL-severe).
The ADCS-ADL-severe is derived from the Alzheimer's Disease Cooperative Study
Activities of Daily Living Inventory, which is a comprehensive battery of ADL questions
used to measure the functional capabilities of patients. Each ADL item is rated
from the highest level of independent performance to complete loss. The ADCS-ADL-severe
is a subset of 19 items, including ratings of the patient's ability to eat,
dress, bathe, use the telephone, get around (or travel), and perform other activities
of daily living; it has been validated for the assessment of patients with moderate
to severe dementia. The ADCS-ADL-severe has a scoring range of 0 to 54 with the
lower scores indicating greater functional impairment. The investigator performs
the inventory by interviewing a caregiver, in this study a nurse staff member, familiar
with the functioning of the patient.
Effects on the SIB:
Figure 7 shows the time course for the change from baseline in SIB score for the
two treatment groups over the 24 weeks of the study. At 24 weeks of treatment, the
mean difference in the SIB change scores for ARICEPT®-treated
patients compared to patients on placebo was 5.9 units. ARICEPT®
treatment was statistically significantly superior to placebo.
Figure 7. Time course of the change from baseline in SIB score for patients completing
24 weeks of treatment.
Figure 8 illustrates the cumulative percentages of patients from each of the two
treatment groups who attained the measure of improvement in SIB score shown on the
X-axis. While patients assigned both to ARICEPT®and to
placebo have a wide range of responses, the curves show that the ARICEPT®group
is more likely to show a greater improvement in cognitive performance.
Figure 8. Cumulative percentage of patients completing 24 weeks of double-blind treatment
with particular changes from baseline in SIB scores.
Figure 9. Time course of the change from baseline in ADCS-ADL-severe score for patients
completing 24 weeks of treatment.
Effects on the ADCS-ADL-severe: Figure 9 illustrates the time course for
the change from baseline in ADCS-ADL-severe scores for patients in the two treatment
groups over the 24 weeks of the study. After 24 weeks of treatment, the mean difference
in the ADCS-ADL-severe change scores for ARICEPT®treated
patients compared to patients on placebo was 1.8 units. ARICEPT®treatment
was statistically significantly superior to placebo.
Figure 10 shows the cumulative percentages of patients from each treatment
group with specified changes from baseline ADCS-ADL-severe scores. While both patients
assigned to ARICEPT®and placebo have a wide range of responses,
the curves demonstrate that the ARICEPT®group is more
likely to show a smaller decline or an improvement.
Figure 10. Cumulative percentage of patients completing 24 weeks of double-blind
treatment with particular changes from baseline in ADCS-ADL-severe scores.
Japanese 24-Week Study
In a study of 24 weeks duration, conducted in Japan, 325 patients with severe Alzheimer's
Disease were randomized to doses of 5 mg/day or 10 mg/day of donepezil, administered
once daily, or placebo. Patients randomized to treatment with donepezil were to
achieve their assigned doses by titration, beginning at 3 mg/day, and extending
over a maximum of 6 weeks. 248 patients completed the study with similar proportions
of patients completing the study in each treatment group. The primary efficacy measures
for this study were the SIB and CIBIC plus.
At 24 weeks of treatment, statistically significant treatment differences were observed
between the 10 mg/day dose of donepezil and placebo on both the SIB and the CIBIC
plus. The 5 mg/day dose of donepezil showed a statistically significant superiority
to pacebo on the SIB, but not on the CIBIC plus.