Note: Descriptions are shown in the official language in which they were submitted.
CA 02310926 2000-06-27
-1-
A USE OF GA:LANTAMINE FOR THE TREATMENT OF
NEUROPSYCHIt~TRIC BEHAVIOUR ASSOCIATED WITH ALZHEIMER'S
DISEASE
The present invention relates to the use of an effective amount of galantamine
for the
treatment of neuropsychiatric behaviour associated with Alzheimer's disease.
BACKGROUND C>F THE INVENTION
Galantamine is a reversible cholinesterase inhibitor that can be isolated from
a number
of different plant sources, including daffodil bulbs. Galantamine interacts
competitively with the enzyme, acetylcholinesterase, and demonstrates a 10 to
50 fold
selectivity for acetyl vs. but:yryl cholinesterase.
Galantamine has been used for the treatment of a number of chronic diseases,
where
life-long treatment rnay be necessary. Galantamine has been shown to be
effective in
the treatment of arthritic disorders (Canadian Patent application 2,251,114);
fatigue
syndromes (Canadian Patent application 2,108,880); mania (Canadian Patent
application 2,062,094);schizophrenia (Canadian Patent application 2,108,880);
memory
dysfunction, including Alzheimer's Disease (United States Patent 4,663,318);
alcoholism (Canadian Patent 2,039,197); nicotine dependence (Canadian Patent
application 2,153,570); disorders of attention (PCT publication WO 99/21561)
and jet
lag (Canadian Patent application 2,193,473).
However, none of the studies demonstrate the usefulness of galantamine for the
treatment of neuropsychiatric behaviour associated with Alzheimer's disease.
SUNINIARY OF Tl-~ INVENTION
Thus, according to the present invention there is provided a use of of
galantamine for
the treatment of neuropsychiatric behaviour associated with Alzheimer's
disease.
CA 02310926 2001-06-12
-2-
In a further embodiment there is provided a method of treating
neuropsychiatric
behaviour associated with Alzheimer's disease by administering to a patient in
need
thereof a safe and effective dose of galanatamine or a pharmaceutically
acceptable salt
thereof.
BRIEF DESCRIPTION OF' THE DRAWINGS
These and other features of the invention will become more apparent from the
following description in which reference is made to the appended drawings
wherein:
FIGURE 1 shows the mean change from baseline by treatment group over time in
ADAS-cog/11 (observed case).
FIGURE 2 shows the mean change from baseline by treatment group over time in
CIBIC'-plus (observed case).
FIGURE 3 shows the cumulative percentage of patients with specified changed
from
baseline at Month 5 in ADAS-cog/11 scores.
FIGURE 4 shows the change: in ADL performance from baseline over time at Month
5.
FIGURE 5 shows the change in NPI score from baseline over time to Month 5.
DESCRIPTION OF PREFERRED EMBODIMENT
The present invention relates 1:o the use of an effective amount of
galantamine for the
treatment of neuropsychiatric: behaviour associated with Alzheimer's disease.
Galantamine, a tertiary alkaloid, has been isolated form the bulbs of the
Caucasian
snowdrops Galantanus woronowi (Proskurnina, N. F. and Yakoleva, A. P. 1952,
Alkaloids of Galanthus woronowi. II. Isolation of a new alkaloid. (In
Russian.)
Zh.Obschchei Khim. (J. Gen. Chem.) 22, 1899-1902). It has also been isolated
from
the common snowdrop Galanthus nivalis (Boit, 1954) Chem. Ber. 87: 724-725.
Galantamine is a well-known acetylcholinesterase inhibitor which is active at
nicotinic
receptor sites but not on muscarinic receptor sites. It is capable of passing
the blood-
brain barrier in humans, and presents no severe side effects in
therapeutically effective
dosages.
CA 02310926 2001-06-12
-3-
Galantarnine has been used extensively as a curare reversal agent in
anaesthetic
practice in Eastern bloc countries (cf. review by Paskow, Galanthamine, Hdbk.
Exp.
Pharmac. 79.. 653-672, 1986) and also experimentally in the West (cf. Bretagne
and
Valetta, "Essais Cliniques en Anesthesiologie D'Un Nouvel
Anticholinesterasique La
Galanthaminf:," Anesth. Analges, 22, 285-292, 1965: Wislicki, "Nivalin
(Galanthamine Hydrobromide), an Additional Decurarizing Agent, Some
Introductory
Observations," Brit. J. Anaesth. 39, 963-968, 1967; Consanitis et al., "A
Comparative
Study of Galanthamine Hydrobromide and Atropine/Neostigmine in Conscious
Volunteers," Der Anaesthesist, 416-421, 1971).
Galantamine has been markexed by the company Waldheim (Sanochemia Gruppe) as
NivalinT"' in Germany and Austria since the 1970s for indications such as
facial
neuralgia.
In the present invention when we refer to galantamine we include within this
term
galantamine itself, derivatives and salts thereof, such as halides, for
example
galantamine hydrobromide.
For the purposes of the present invention galantamine and derivates and salts
thereof
may be formulated according to convention methods of pharmacy, together where
appropriate with one or more pharmaceutically acceptable carriers, excipients
or
diluents, as is known in the art. Such formulations can take the form of
tablets,
capsules, solutions, or lozenges, pessaries, creams, suppositories or
transdermal
formulations, depending on the route of administration.
Galantamine has been used for the treatment of a number of chronic diseases,
where
life-long treatment may be necessary. Galantamine has been shown to be
effective in
the treatment of arthritic disorders (Canadian Patent application 2,251,114);
fatigue
syndromes (Canadian Patent application 2,108,880); mania (Canadian Patent
application 2,062,094); sclaizophrenia (Canadian Patent application
2,108,880);
memory dysfunction, including Alzheimer's Disease (United States Patent
4,663,318);
alcoholism (Canadian Patent 2,039,197); nicotine dependence (Canadian Patent
application 2,153,570); disorders of attention (PCT publication WO 99/21561)
and jet
lag (Canadian Patent application 2,193,473).
CA 02310926 2000-06-27
-4-
According to the present invention a safe and effective amount of galantamine
can be
used for the treatment of neuropsychiatric behaviour associated with
Alzheimer's
disease.
Precise dosage rates and regimes can be determined empirically by the medical
practitioner, depending on individual circumstances. For example, if the
compound
is delivered orally, a daily dose of about 1 mg to about 100 mg. In a further
example
the compound can be delivered at about 5 mg to about 50 mg per day. In yet a
further
example the compound can be delivered at about 16 mg to about 32 mg per day.
Precise daily dosages can be; selected from 16 mg, 18 mg, 24 mg or 32 mg per
day.
It is preferred that the daily dosage be divided into two or three equal
dosages.
In one embodiment of the present invention it has been found that the
tolerability or
safety of the drug can be improved if the patient is introduced to the drug
slowly over
a number of weeks.
In one embodiment of the present invention the patient is introduced to
galantamine
slowly from about 2 weeks to about 10 weeks, wherein the dose is increased
over this
period.
In one embodiment of the present invention the patient receives a dose of
about 8
mg/day for about 1 week, followed by a dose of about 16 mg/day for about 1
week,
followed by a maintenance dose of about 24 mg/day thereafter.
In one embodiment of the present invention the patient receives a dose of
about 8
mg/day for about 1 week, followed by a dose of about 16 mg/day for about 1
week,
followed by a dose of about 24 mg/day for about a week, followed by a
maintenance
dose of about 32 mg;/day thereafter.
In one embodiment of the present invention the patient receives a dose of
about 8
mg/day for from about 2 weeks to about 4 weeks, followed by a dose of about 16
CA 02310926 2000-06-27
-$-
mg/day for from af~out 2 weeks to about 4 weeks, followed by a maintenance
dose of
about 24 mg/day thereafter.
In one example of this embodiment the patient receives a dose of about 8
mg/day for
about 4 weeks, followed by a dose of about 16 mg/day for about 4 weeks,
followed by
a maintenance dose of about 24 mg/day thereafter.
In a further embodiment of the present invention the patient receives a dose
of about
8 mg/day for from about 2 'weeks to about 4 weeks, followed by a maintenance
dose
of about 16 mg/day thereafter. In one example of this embodiment the patient
receives
a dose of about 8 m;;/day for about 4 weeks, followed by a maintenance dose of
about
16 mg/day thereafter.
According to the present invention, the neuropsychiatric behaviour associated
with
Alzheimer's Disease includes for example: delusions, hallucinations,
agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition,
irritability/lability and aberrant motor behavior.
The present invention is illustrated by the following example, which is not to
be
construed as limiting.
EXAMPLES
Patients diagnosed vvith Alzheimer's Disease (approximately 910) were
randomized to
one of four treatment arms: placebo; 8 weeks titration to galantamine 24
mg/day; 4
weeks titration to l;alantamine 16 mg/day, or galantamine 8 mg/day, no
titration
needed, for five months. Patients included in this study must have been
diagnosed with
Alzheimer's Disease, had an Alzheimer's Disease Assessment Scale (Rosen, W.G.
et
al., Amer. J. Psychiatry, 14.1: 1356- 1364, 1984) cognitive portion (ADAS-cog-
11)
score of at least 18 and had a history of cognitive decline that was gradual
at the onset
and progressive over a period of at least six months.
CA 02310926 2000-06-27
-6-
The titration schedules for the various treatment arms are as follows:
Subjects in the Plac;ebo group received 21 weeks (5 months) of placebo
medication.
Subjects in group Gal 24 received 4 weeks of 8 mg/day galantamine (4 mg, twice
daily
(bid)), 4 weeks of 16-mg/day galantamine (8 mg, bid) and 13 weeks of 24 mg/day
galantamine (12 m~;, bid). Subjects in group Gal 16 received 4 weeks of 8
mg/day
galantamine (4 mg, bid) and 17 weeks of 16-mg/day galantamine (8 mg, bid).
Subjects
in group Gal 8 received 8 mg/day (4 mg, bid) immediately upon randomization
and
continued on that dose for 21 weeks.
All patients were .monitored throughout the study, with follow-up and
cognitive
evaluation at four cheeks, three months and five months after the start of the
study.
The primary efficacy endpoints were the change from baseline ADAS-cog/11 and
the
CIBIC-plus score (~Cliniciar~'s Interview Based Impression of Change Plus
Family
Input) at month five . These t:wo tests together with the Mini-Mental State
Examination
(MMSE), which was performed at the screening stage, are discussed below:
The ADAS consists of two parts -- a cognitive subscale and a behavioral
subscale. The
behavioral subscale was not lie used in this study. The cognitive subscale,
the ADAS--
cog-11, consisted of Word Recall and Word Recognition memory tests, Object and
Finger Naming, Commands,, Constructional Praxis, Ideational Praxis,
Orientation,
Remembering Test l(nstructions, Spoken language Ability, Comprehension of
Spoken
language and Word Finding Difficulty was the primary variable in this study.
In addition to the above specified items from the ADAS-cog-11, two additional
ADAS
items were assessed: The Concentration and Distractibility item, originally
part of the
behavioral subscale, was performed and a Delayed Word Recall test (delayed
recall of
the word recall items) was added to give additional information regarding
cognitive
status. The expandf:d 13 item ADAS (ADAS-cog 13) was a secondary variable.
CA 02310926 2000-06-27
To reduce variability due to circadian fluctuations in cognitive status the
ADAS was
done always at the same time of the day, preferably before noon. Only a
trained
ADAS rater performed the test. Ideally the ADAS rater was not involved in the
treatment of the subject and should have no access to AE (adverse event)
reporting.
The ADAS was performed at visits 1, 2, 3, 4 and 5 (screening, baseline, week
4, week
13 and month 5 or upon early discontinuation of trial medication intake). For
word
recall and word recognition two parallel wordlists, list A and list B were
employed.
List A was used at visits 1 and 3, List B at visits 2, 4, and 5 or upon early
discontinuation of trial medication intake. For practical reasons the words
for word
recognition was presented only once. The total score of the 11 cognitive items
on the
original ADAS cognitive subscale (ADAS-cog/11, Range: 0-70) was recorded.
The CIBIC-plus score was a second primary variable. An independent,
experienced
and properly trained clinician provided a global impression of the subject's
deterioration or improvement over the course of the trial, based on separate
interviews
with the subject and caregivers. If helpful, the CIBIC rater audiotaped or
videotaped
the baseline interview for future reference.
Change from baseline was rated on an 7 point scale, where 1 indicates markedly
improved, 4 indicate, no change and 7 indicates markedly worse. The CIBIC-plus
was
performed at visit ~ , 3, 4, and S (baseline, week 4, week 13, and month 5 or
upon
early discontinuation of trial :medication intake). Only a trained CIBIC rater
performed
the test.
The MMSE is a veer brief test of cognitive functions including orientation to
time and
place, instantaneous recall, short-term memory, and ability to perform serial
subtractions or reverse spelling, constructional capacities and the use of
language. The
MMSE score was derived from the sum of the points assigned to each completed
task.
A total possible score is 30. The MMSE will be performed at visit
1(screening).
CA 02310926 2000-06-27
_$-
Secondary efficacy variables include ADAS-cog/11 and the ADCS/ADL scale . The
ADCS/ADL test is discussed below:
The ADCS/ADL scale is a 23-item informant-based assessment scale measuring
widely
applicable daily activities appropriate for patients in the mild to moderate
category of
Alzheimer's Disease. The 23 items were selected for measurement from the
larger set
of 45 items studied by Galasko et al (Alzheimer Disease and Associated
Disorders, Vol
11, Suppl. 2, 1997j. These individual items were scored from 0-3 to 07,
depending
on the question, with a possible total score of 78. A higher score indicated a
higher
functioning patient.
The items and scoring were as follows:
Eating (0-3)
Walking (0-3)
Toileting (0-3)
Bathing (0-3)
Grooming (0-3)
Dressing
selection of ~~lothes (0-3)
physical per:Formancf: (0-4)
Telephone (0-5)
Television (0-3)
Conversation (0-3)
Dishes (0-3)
Managing personal belongings (0-3)
Obtaining beverages (0-3)
Making a meal or snack (0-~G)
Disposal of garbage (0-3)
Travel outside homf: (0-4)
Shopping (0-4)
Keeping appointments (0-3)
CA 02310926 2000-06-27
-9-
Ability to be left alone (0-3)
Current events (0-3 )
Reading (0-2)
Writing (0-3)
Hobbies (0-3)
Household appliances (0-4)
Neuropsychiatric bf;havior was monitored by a test known as The
Neuropsychiatric
Inventory (NPI) (Cummings, J.L. et al., Neurology, 44: 2308-2314, 1994). The
NPI
covers 10 domains of behaviors reported in patients with Alzheimer's Disease:
delusions, hallucinations, agitation/aggression, dysphoria, anxiety, euphoria,
apathy,
disinhibition, irritability/lability and aberrant motor behavior. For each
domain
abnormal behavior c:an be absent (score 0) or present. If present, the
frequency and
severity of abnorm;~l behavior is rated based on answers to a set of
subquestions
regarding behavior; relevant to that domain. Severity was rated 1 to 3 as
mild,
moderate or marked. Frequency was rated 1 to 4 as occasionally, often,
frequently and
very frequently. The product of frequency and severity (maximum score = 12)
was
calculated for each domain. A total of NPI was calculated as the sum of the
frequency
and severity produces (maximum score = 120). The NPI was performed at visits
2,
3, 4 and 5 (baseline., week 4, week 13, and month S or upon early
discontinuation of
trial medication).
All data was compared among the treatment groups - placebo, galantamine 8
mg/day,
16 mg/day and 24 mg/day.
Between treatment ;groups comparisons (with particular focus on differences
from
placebo) were done at each scheduled time interval and for each endpoint
imputation
scheme. These comparisons will be based on the change from baseline scores for
efficacy parameters with baseline (e.g., ADAS-cog/11) and the original scored
for
efficacy parameters without 'baseline e.g., CIBIC-plus).
CA 02310926 2000-06-27
-10-
For continuous data., a two-way analysis of variance (ANOVA) model with
treatment
and investigator as factors were used to compare the treatment groups for the
change
from baseline data. The interaction between treatment and investigator was
examined.
The impact of the baseline score on change from baseline was evaluated. If the
S baseline score was found to be a relevant predictor (p < 10), an analysis of
covariance
model (ANCOVA) 'was used to assess the treatment effects and the interaction
between
treatment and baseline score was examined. If the parametric methods were
deemed
inappropriate (normality assumption violated), nonparametric methods such as
two-way
ANOVA on rankedi data, Van Elteren test, controlling for investigator, was
used.
Following ANOV~?,, Fisher's LSD procedure was used for pairwise comparisons
between each galanthamine group and the placebo group. A linear contrast on
the
main effect for trea~:ment was used to test the dose response relationship.
For ordinal categorical variables such as the CIBIC-plus score, the Van
Elteren test
controlling for investigator was used for the between group comparison. For
the
nominal data (e.g. , events rates), the Cochran-Mantel-Haenszel test for
general
association controlling for investigator was used. A linear contrast on the
proportion
of patients that stay the same or improve was used to test for increasing
response with
increasing dose.
If a significant proportion of subjects discontinue prematurely, additional
analyses were
preformed to evaluate the impact on the results. In addition to the by-visit
analysis,
method for analysin~; continuous repeated measures were used to evaluate the
treatment
effect over time.
The safety of the drug was also monitored throughout the study. Blood samples
for
biochemistry and haematology and random urine sample for urinalysis were taken
at
each visit and at completion for all efficacy testing. Systolic and diastolic
blood
pressure were measured in tlae sitting position, pulse and vital signs were
recorded at
each visit.
CA 02310926 2000-06-27
-11-
Patient Demographics and baseline characteristics were to be well balanced
across all
treatment groups (T'able 1). The baseline cognitive performance for these
Alzheimer's
disease patients was mild to moderate as measured by the MMSE and ADAS-cog/11
scores of approximately 18 and 28 to 20.
Table 1: Demographics and baseline characteristics
Trial disposition
and
atient characteristicsPlacebo GAL 8 m GAL 16 GAL 24
m m
Total Number 286 140 279 273
of Patients
Completed: N 2,40 (84 108 (77 219 (79 212 (78
( % ) % ) % ) % ) % )
Gender
Male 108 (38 50 (36 % 105 (38 90 (33
% ) ) % ) % )
Female 178 (62 90 (64 % 174 (62 183 (67
% ) ) % ) % )
Age: (Years)
Mean (SE) 77.1 (0.46)76.0 (0.61)76.3 (0.49)77.7 (0.43)
Median (Min-Max.)78 (53-100)77 (52-91) 77 (51-94)78 (57-95)
Race
Black 13 5 12 14
Caucasian 267 (93 132 (94 260 (93 249 (91
% ) % ) % ) % )
Hispanic 3 3 5 4
Oriental 3 0 1 3
Other 0 0 1 3
Sum of MMSE:
Mean (SE) 1'7.7 (0.21)18.0 (0.30)17.8 (0.21)17.7 (0.23)
Median (Min-Max)19 (10-22) 19.0 (10-22)19 (10-22)19.0 (10-22)
Baseline ADAS-
cog/11 -- 29.4 (0.63)27.8 (0.94)29.4 (0.66)29.0 (0.67)
Mean (SE) 27 (10-61) 26 (11-62) 28 (10-62)27 (10-54)
Median (Min-Max)
The number of patients randomized among the four treatment groups was 978. The
total number of patients completing this trail was high (approximately 80 % )
with a
relatively even rate of discontinuation due to adverse events was relatively
infrequent
and evenly distributed among all treatment groups (see Table 2).
CA 02310926 2000-06-27
-12-
Table 2: Iliscontinuation of trial medication
Trial termination reasonsPlacebo GAL GAL GAL
8 m /da 16 m /da 24 m
/da
Total patients 286 140 279 273
Total completed: N 240 (84 108 (77 219 (79 212 (78
( ~o ) %) % ) % ) % )
Total discontinued 46 ( 16 32 (23 60 (22 61 (22
(DC): N ( % ) % ) % ) % ) % )
DC due to adverse c;vent20 (7 9 (6 % 19 (7 27 (
% ) ) % ) 10 %
)
DC due to inefficacy 0 1 (1 % 0 2 (1
) %)
DC due to other' 23 (8 18 ( 13 29 ( 10 20 (7
% ) % ) % ) % )
DC due to ineligible: 0 0 4 (1 % 2 (1
to continue ) %)
DC due to non-compliance3 ( 1 4 (3 % 7 (3 % 10 (4
% ) ) ) % )
DC due to withdrawal 0 0 1 (0.4 0
of consent % )
a: The majority of discontinuations due to other reasons were for withdrawal
of consent.
In this study there were two primary efficacy endpoints according to widely
used
international standards: change in ADAS-cog/11 score at Month 5 compared to
baseline and CIBIC-plus scare at Month 5.
As shown in Table 3 and Figure 1, a statistically significant treatment effect
was shown
for the 16 and 24 m~;/day galantamine treatment groups compared with placebo
for the
ADAS-cog/11. Re;~ults from analysis based on the last observation carried-
forward
(LOCF) data cor~ob~~rate the result based on observed data. The 8 mg/d~y
galantamine
group was significantly different from placebo for the observed case but not
for the
LOCF. Galantamin.e at a dose of 24 mg/day did not appear to be significantly
more
effective than 16 rrtg/day. However, the duration of exposure to the target
dose
differed by 1 month between the two treatment groups (two months versus three
months respectively).
CA 02310926 2000-06-27
-13-
Table 3: Change from baseline in ADAS-cog/11 at Month 5
Placebo GAL 8mg GAL l6mQ GAL 24me
Month 5: (observedn=225 n=101 n=208 n=211
case)
Mean (SE) 1.8 (0.43)0.1 (0.58)*-1.5 (0.40)***t-1.8 (0.44)***t
Month 5: (LOCF) n=255 n=126 n=253 n=253
Mean (SE) 1.7 (0.39)0.4 (0.52)0-1.4 (0.35)***~-1.4 (0.39)***~
Lower score matcates better condttton. Y-Values based on two-way ANOVA model.
Significantly n;.ore effective than placebo: *: ps0.05; **: ps0.01; ***:
ps0.001; Approached
significance: 0: 0.05 <: p-value < 0.10.
~ Significantly rr,ore effective than 8 mg/day: t: ps0.05; t: ps0.01.
For the CIBIC-plus assessment at Month 5, the percent of patients with
improved or
unchanged scores was sig:nifucantly greater with galantamine treatment with 16
or 24
mg/day compared with placebo or 8 mg/day of galantamine (Table 4). After 5
months
of treatment, 64 % to 68 % of patients with 24 or 16 mg/day of galantamine
showed
improvement or were unchanged from baseline compared with 47 % to 51 % with
placebo or 8 mg/day of galantamine. The analysis of imputed data at LOCF
endpoint
gave similar results. There was an apparent dose-related increase in the
percentage of
patients showing improvement or no change in the CIBIC-plus (Figure 2).
Table 4: CIBIC-plus at Month 5 for improved or unchanged scores
Placebo GAL 8 mg GAL 16 mg GAL 24 mg
Month 5: (observed.n=:237 n=106 n=212 n=212
case)
Im roved/no char 11:? (47%)54 (51%) 143 (68%)***t136 (64%)***#
a n~;%)
Month 5: (LOCF) n=263 n=128 n=255 n=253
Improved/no change1213 (49 68 (53 169 (66 162 (64
n~; % ) % ) % ) % )***t % )***t
P-value from Van Elteren test on the 7-point scale
Significantly more effective than placebo: *: ps0.05; **: ps0.01; ***:
ps0.001.
Significantly more effective than 8 mg/day: t: ps0.05; $: ps0.01.
At Month 5 there were significantly more patients who responded with no change
or
improved scores wish 16 and 24 mg/day of galantamine compared with placebo or
8
mg/day of galantamine. Patients responding with ADAS-cog/ 11 changes from
baseline
of 7 or more points occurred in 15.9 % and 22.3 % of patients in the 16 and 24
mg/day
CA 02310926 2000-06-27
-14-
groups, respectively, compared with the placebo group (7.6%). There was
overall a
higher cumulative percentage of patients with galantamine treatment who
responded
with a minimum irrtprovement of any magnitude compared with placebo (Figure
3).
Table 5: Rfsponders analysis based on change in ADAS-cog/11 score
from baseline at Month 5
Definition of Placebo GAL 8 mg GAL 16 mg GAL 24 mQ
res ondc:=
n=225 n=101 n=208 n=211
Changes0 points 94 (41.8) 47 (46.5) 136 (65.4)***#137 (64.9)***$
n (%.)
Changes-4 points44 (19.6) 26 (25.7) 74 (35.6)***078 (37.0)***t
n (~o)
Changes-7 pointsll7 (7.6) 14 (13.9) 33 (15.9)**47
n (fib) (22.3)***0
Changes-10 points8 (3.6) 6 (5.9) 15 (7.2) 22 ( 10.4)**
n ( % )
Y-value based on (:MH test
Significantly higher percentage of responders than placebo: *: ps0.05; **:
ps0.01;
***: ps0.001;
Significantly higher percentage of responders than 8 mg/day: t: ps0.05; $:
ps0.01;
Approached ~;ignificance: 0: 0.05 < p-value < 0.10;
The differen<:e berivee;n 16 and 24 mg/day approached significance ~: 0.05 < p-
vlaue < 0.10.
An additional secondary indication captures overall changes in Activities of
daily
Living (ADL) performances as measured by the Alzheimer's Disease Cooperative
Study Activities of lJaily Living (ACDS/ADL) scale. As mentioned above this
scale
is comprised of 23 items that have been tested and validated in patients with
mild to
moderately severe ~~lzheilner's disease.
Galantamine treatment with 16 or 24 mg/day for 5 months was statistically more
effective in maintaining the ADL total score at baseline levels than treatment
with
placebo or 8 mg/day of galantamine (Table 6). The dose-related effect of
galantamine
treatment is apparer.~t in Figure 4 that shows change of total ADL score over
time.
CA 02310926 2000-06-27
-15-
Table 6: (:hange in Total ADL score from baseline at Month 5
Placebo GAL 8 mg GAL 16 m~ GAL 24
m
Month 5: (observedn=235 n=106 n=212 n=212
case)
Mean (SE) -4.0 (0.59)-3.1 (0.91)-0.5 (0.55)***t-1.6 (0.61)**
Month 5: (LOCF) n=262 n=129 n=255 n=253
Mean (SE) -3.8 (0.55)-3.2 (0.79)-0.7 (0.050)***~-1.5 (0.56)**
ritgner score matcates oetter conanton. r-values based on two-way ANOVA model.
Significantly more effective than placebo: **: p_<0.01; ***: ps0.001
Significantly more effective than 8 mg/day: t: p<_0.05; $: p<_0.01.
There was a statistically significant (p < 0.05) benefit seen in the change in
the total
NPI score at Month 5 relative to baseline for 16 and 24 mg/day of galantamine
compared with a deterioration with placebo or 8 mg/day of galantamine (Table 7
and
Figure 5). An increase in score indicated a worsening in condition. Thus, a
maintenance of neunopsychiatric behaviour was observed with galantamine at 16
and
24 mg/day.
Table 7: Change in Total NPI score from baseline at Month 5
Placebo GAL 8 m GAL 16 m GAL 24
'm
Month 5: (observedn=234 n=106 n=211 n=212
case)
Mean (SE) 2.3 (0.74)2.3 (1.121)-0.1 (0.76)*-0.1 (0.86)*
Month 5: (LOCF) n=262 n=129 n=255 n=253
Mean (SE) ~ 2.0 (0.68)2.3 (1.00) -0.1 (0.71)*-0.0 (0.76)*
Higher score indicates worsened condition. p-Values based on two-way ANOVA
model.
~ Significantly more effective than placebo: *: p~0.05
The most common adverse events were evenly distributed across treatment groups
with
the exception of events that are associated with cholinomimetic agents (Table
8). Of
these related event s, nausea, vomiting and anorexia showed a mild dose-
related
occurrence at a rela~:ively low incidence.
CA 02310926 2000-06-27
-16-
Table 8: Incidence of most frequent (z5%) adverse events: number (%) of
patients
Adverse event Placebo GAL 8 mg GAL 16 mg GAL 24
(Preferred mg
term)
Total all patients286 140 279 273
Nausea 13 (4.5%) 8 (5.7%) 37 (13.3%) 45 (16.5%)
Vomiting 4 (1.4%) 5 (3.6%) 17 (6.1 27 (9.9%)
%)
Anorexia 9 (3.1 8 (5.7 % 18 (6.5 24 (8.
% ) ) % ) 8 % )
Agitation 2'7 (9.4 21 ( 15.0 28 ( 10.0 22 (8.1
% ) % ) % ) % )
Depression 1:5 (5.2%)4 (2.9%) 24 (8.6%) 22 (8.%)
Urinary tract 19 (6.6 11 (7.9 23 (8.2 22 (8.1
infection %) % ) % ) % )
Dizziness 10 (3.5 7 (5.0 % 15 (5.4 19 (7.0
% ) ) % ) % )
Injury 1:? (4.2%)5 (3.6%) 12 (4.3%) 16 (5.9%)
Diarrhea 1'7 (5.9 7 (5.0 % 34 ( 12.2 15 (5.5
% ) ) % ) % )
Dyspepsia 7 (2.4%) 4 (2.9%) 13 (4.7%) 15 (5.5%)
Headache 1:3 (4.5%)5 (3.6%) 19 (6.8%) 13 (4.8%0
Weight decrease 4 (1.4%o) 2 (1.4%) 15 (5.4%) 13 (4.8%)
Fall 14 (4.9 11 (7.9 14 (5.05 12 (4.4
% ) % ) % ) % )
Rhinitis 6 (2.1 9 (6.4 % 9 (3.2 % 11 (4.0
% ) ) ) % )
Edema peripheral7 (2.4 9 (6.4 % 8 (2.9 % 7 (2.6
% ) ) ) % )
For most adverse events of clinical interest, as shown in Table 9, there were
either no
differences or slight dose-related differences between treatment groups. For
bradycardia, there was a higher incidence for patients treated with
galantamine
compared with placebo but there was no dose-related association apparent. For
syncope, there was a slight dose-related increase in incidence with 24 mg/day
of
galantamine, however 3 of these cases occurred at a lower dose during
titration, and
are therefore attributable to a lower galantamine dose. Consequently, the
incidences
shown in Table 6 arE: very likely to be over-estimates for the occurrence of
syncope at
the higher doses. Furthermore, 10 of 18 patients who experienced a syncopal
episode
were taking concomitant cardiovascular medication including bata-blockers,
calcium
channel antagonists, ACE inhibitors, and/or diuretics. Of these 18 patients,
11 had
CA 02310926 2000-06-27
- 1~ -
active cardiovascular disease listed in their past medical history. Therefore,
a majority
of patients who experienced syncope had either a cardiovascular condition or
were
taking cardiovascular medication.
Table 9: Adverse events of clinical interest
Adverse events Placebo GAL 8 mg GAL 16 GAL 24
(Prefe:rred mg mg
term)
Total all patients286 140 279 273
Bradycardia 1 (0.3 5 (3 .6 7 (2.5 8 (2.9
% ) % ) % ) % )
Convulsions 2. (0.7 0 0 1 (0.4
% ) % )
Fatigue 6 (2.1 3 (2.1 10 (3.6 13 (4.8
% ) % ) % ) % )
Muscle weakness 3 ( 1.0 1 (0.7
% ) 3 (1.1%) 1 (0.4%)
Syncope 2 (0.7%) 2 (1.4%) 5 (1.8%) 9 (3.3%)
The incidence of serious adverse events was comparable across all treatment
groups
and (with the excepoion of syncope) showed no dose-related trends (Table 10).
The
four most frequent ~,erious adverse events with galantamine and with an
incidence of
at least 1 % of patients in any group were injury, syncope, fall, and
myocardial
infarction. There ware no dose-related increases in GI-related serious adverse
events.
The only serious adverse event that showed a dose-relationship was syncope,
however,
for reasons already ;provided, these rates may be an over-estimate.
CA 02310926 2000-06-27
-18-
Table 10: Serious adverse events (with z 2 patients in any group)
Adverse Event (PreferredPlacebo GAL 8 mg GAL 16 GAL 24 mg
term) mg
Total all patients286 140 279 273
Total patients 31 ( 10. 14 ( 10.0 28 ( 10.0 35 ( 12.8
with amr SAE 8 % ) % ) % ) % )
Injury 4 (1.4%) I (0.7%) 1 (0.4%) 5 (1.8%)
Syncope 2 (0.7%) 1 (0.7%) 4 (1.4%) 5 (1.8%)
Asthenia 1 (0.3 0 (0.0 2 (0.7 1 (0.4 %
% ) % ) % ) )
Dyspnea 1 (0.3 0 (0.0 2 (0.7 3. ( 1.1
% ) % ) % ) % )
Pneumonia 4 ( 1.4 1 (0.7 2 (0.7 3 ( 1.1
% ) % ) % ) % )
Gi haemorrhage 0 (0.0 0 (0.0 0 (0.0 2 (0.7 %
% ) % ) % ) )
Vomiting 1 (0.3 0 (0.0 2 (0.7 1 (0.4 %
% ) % ) % ) )
Abdominal pain 1 (0.3 0 (0.0 2 (0.7 0 (0.0 %
% ) % ) % ) )
Diarrhea 1 (0.3 0 (0.0 3 ( 1.1 0 (0.0 %
% ) % ) % ) )
Nausea I (0.3 0 (0.0 2 (0.7 0 (0.0 %
% ) % ) % ) )
Basal cell carcinomaI) (0.0 0 (0.0 0 (0.0 2 (0.7 %
% ) % ) % ) )
Breast neoplasm :? (0.7 0 (0.0 0 (0.0 0 (0.0 %
female % ) % ) % ) )
Fall :3 (1.0%)4 (2.9%) 1 (0.4%) 3 (1.1%)
Surgical intervention1 (0. 0 (0.0 3 ( 1.1 0 (0.0 %
3 % ) % ) % ) )
Thrombophlebitis I (0.3 0 (0.0 0 (0.0 2 (0.7 %
deep % ) % ) % ) )
Transient ischemic1 (0. 1 (0.7 2 (0. 7 0 (0.0 %
attack 3 % ) % ) % ) )
Myocardial infarction2 (0.7 3 (2.1 1 (0.4 1 (0.4 %
% ) % ) % ) )
Agitation l (0.3 2 ( 1.4 1 (0.4 0 (0.0 %
% ) % ) % ) )
Urinary tract infecti~~n0 (0.0 1 (0.7 2 (0.7 0 (0.0 %
% ) % ) % ) )
Cardiac failure 'L (0.7 0 (0.0 3 ( 1.1 0 (0.0 %
% ) % ) % ) )
Dehydration 0 (0.0 0 (0.0 3 ( 1.1 0 (0.0 %
% ) % ) % ) )
Sepsis :? (0.7 0 (0.0 0 (0.0 0 (0.0 %
% ) % ) % ) )
Throughout the trial there were 11 deaths. There was no apparent dose-related
patterns
in the occurrences o~E deaths. No death was considered by the investigator to
be related
to trail medication.
CA 02310926 2001-06-12
-19-
The results of this example confirmed that treatment with either 16 mg/day or
24/mg
day of galantamine leads to statistically significant improvement in
neuropsychiatric
behaviour, as determined by the NPI score at month 5 relative to baseline with
16
mg/day and 24 mg/day compared with a deterioration with placebo or 8 mg/day of
galantamine.
The present invention has been described with regard to preferred embodiments.
However, it will be obvious to persons skilled in the art that a number of
variations
and modifications can be made without departing from the scope of the
invention as
described in the following claims.
