HUP0300566A2 - A use of galantamine for the treatment of neuropsychiatric behaviour associated with alzheimer's disease - Google Patents

Abstract

Galantamine is used in the treatment of many chronic diseases. Agalantamine can also be used effectively and safely in Alzheimer's disease therapy. Alzheimer's disease is usually accompanied by neuropsychiatric disorders. In the present invention, it is demonstrated that galantamine can be effectively used in patients with Alzheimer's disease in reducing the frequency of occurrence of neuropsychiatric behaviors or in stabilizing the neuropsychiatric status. HE

Description

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PUBLICATION COPY

Use of galantamine in the treatment of neuropsychiatric behaviors associated with Alzheimer's disease

The present invention relates to the use of an effective amount of galantamine for the preparation of a pharmaceutical composition for the treatment of neuropsychiatric behaviors associated with Alzheimer's disease.

State of the art

Galantamine is a reversible cholinesterase inhibitor that can be extracted from various plants, such as the narcissus tuber. Galantamine competitively inhibits the enzyme acetylcholinesterase and has a selectivity of 10-50 times for acetylcholinesterase over butyrylcholinesterase.

Galantamine is used in the treatment of a number of chronic diseases where lifelong therapy is required. Galantamine has been shown to be effective in arthritic diseases [Canadian Patent Application No. CA 2,251,114], fatigue syndromes [Canadian Patent Application No. CA 2,108,880], mania [Canadian Patent Application No. CA 2,062,094 sza97421-3689 Sl mu], schizophrenia [Canadian Patent Application No. CA 2,108,880], memory disorders, including Alzheimer's disease [US Patent No. 4,663,318], alcoholism [Canadian Patent Application No. CA 2,039,197], nicotine addiction [Canadian Patent Application No. CA 2,153,570], concentration disorders [WO 99/21,561] and jet lag [CA Canadian Patent Application No. 2,193,473].

However, none of the publications mention the efficacy of galantamine in the treatment of neuropsychiatric behaviors associated with Alzheimer's disease.

Summary of the invention

The present invention relates to the use of galantamine for the preparation of a pharmaceutical composition for the treatment of neuropsychiatric behaviors associated with Alzheimer's disease.

In a further embodiment, the present invention also relates to a method of treating neuropsychiatric behaviors associated with Alzheimer's disease, comprising administering a safe and therapeutically effective amount of galantamine or a pharmaceutically acceptable salt of galantamine to a patient in need thereof. Brief Description of the Figures

These and other features of the invention can be more precisely understood from the specification, which includes references to the accompanying drawings, which are as follows:

Figure 1 - shows the mean changes from baseline in the treatment group over time on the ADAS-cog/11 rating scale (observed case).

Figure 2 - shows the mean changes from baseline in the treatment group over time on the CIBIC-plus rating scale (observed case).

Figure 3 - shows the cumulative percentage of patients with a defined difference from baseline on the ADAS-cog/11 scale at month 5 of treatment.

Figure 4 - shows the change in ADL scores from baseline over the course of 5 months.

Figure 5 - shows the change in NPI scores from baseline over the course of 5 months.

Preferred embodiments of the invention

The present invention relates to the use of an effective amount of galantamine for the treatment of neuropsychiatric behaviors associated with Alzheimer's disease.

Galantamine is a tertiary alkaloid isolated from the tuber of the Caucasian snowdrop (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. Chern.) 22:1899-19021. Galantamine has also been isolated from the common snowdrop (Galanthus nivalis) [Boit,1954], Galantamine is a well-known acetylcholinesterase inhibitor that acts on nicotinic receptors but not on muscarinic receptors. It crosses the blood-brain barrier in humans and has no serious side effects at therapeutically effective doses.

Galantamine is widely used in Eastern bloc countries [Paskow (1986)] and experimentally in Western countries [Bretagne and Valetta (1965); Wislicki (1967); Consanitis (1971)] as an antidote to curare in general anesthesia.

Galantamine has been marketed in Germany and Austria under the name Nivalin™ by the Waldheim company (Sanochemia group) since 1970 for indications such as facial neuralgia.

In the present invention, the term "galantamine" is intended to mean galantamine itself, its derivatives and salts, such as halide salts, for example galantamine bromide.

For use in the present invention, galantamine, its derivatives and salts may be formulated into a pharmaceutical composition by conventional pharmaceutical methods, optionally with one or more pharmaceutically acceptable excipients, excipients or diluents known in the art. Such a pharmaceutical composition may be, for example, a tablet, capsule, solution or lozenge, suppository, cream, suppository or transdermal preparation, depending on the route of administration.

Galantamine is used in the treatment of a number of chronic diseases where lifelong therapy is required. Galantamine has been shown to be effective in arthritic diseases [Canadian Patent Application No. CA 2,251,114], fatigue syndromes [Canadian Patent Application No. CA 2,108,880], mania [Canadian Patent Application No. CA 2,062,094], schizophrenia [Canadian Patent Application No. CA 2,108,880], memory disorders including Alzheimer's disease [US Patent No. 4,663,318], alcoholism [Canadian Patent Application No. CA 2,039,197], nicotine addiction [Canadian Patent Application No. CA 2,153,570], concentration disorders [WO 99/21,561] and jet lag disorders [CA Canadian Patent Application No. 2,193,473].

According to the present invention, galantamine can be safely and effectively used to treat neuropsychiatric behaviors associated with Alzheimer's disease.

The precise dosage values and regimens can be determined empirically by the practitioner based on the individual circumstances. For example, when the active ingredient is administered orally, the daily dosage may range from about 1 mg to about 100 mg. In another example, the daily dosage may range from about 5 mg to about 50 mg. In a further example, the daily dosage of the compound may range from about 16 mg to about 32 mg. Precise daily dosage may be achieved, for example, by administering 16 mg, 18 mg, 24 mg, or 32 mg per day. It is preferred that the daily dosages be administered in 2 or 3 equal divided doses.

In one embodiment of the present invention, it has been found that the tolerability and safety of the active ingredient can be increased by gradually acclimating the patient to the active ingredient over a period of weeks.

According to another embodiment of the present invention, the patient is accustomed to the active ingredient with gradually increasing doses over periods of 2-10 weeks.

In another embodiment of the present invention, the patient receives about 8 mg of the active ingredient per day for 1 week, then about 16 mg per day for 1 week, and then a maintenance dose of about 24 mg per day thereafter.

In another embodiment of the present invention, the patient receives a maintenance dose of about 8 mg of the active ingredient per day for 1 week, then about 16 mg per day for 1 week, then about 24 mg per day for 1 week, and then about 32 mg per day thereafter.

In another embodiment of the present invention, the patient receives about 8 mg of the active ingredient per day for about 2 to about 4 weeks, then about 16 mg per day for about 2 to about 4 weeks, and then a maintenance dose of about 24 mg per day thereafter.

An example of this embodiment is where the patient receives about 8 mg of the active ingredient for about 4 weeks, then about 16 mg for about 4 weeks, and then a maintenance dose of about 24 mg per day thereafter.

In another embodiment of the present invention, the patient receives about 8 mg of the active ingredient per day for about 2 to about 4 weeks, followed by a maintenance dose of about 16 mg per day thereafter. An example of this embodiment is where the patient receives about 8 mg of the active ingredient per day for about 4 weeks, followed by a maintenance dose of about 16 mg per day thereafter.

In the present invention, neuropsychiatric behaviors associated with Alzheimer's disease include delusions, hallucinations, restlessness/aggressiveness, depression, anxiety, euphoria, apathy, disinhibition, irritability/lability, and aberrant motor behavior.

The present invention is illustrated by examples without limitation.

Examples

Patients with diagnosed Alzheimer's disease (approximately 910 patients) were randomly assigned to one of four treatment groups: placebo; escalating doses of galantamine to 24 mg/day over 8 weeks; escalating doses of galantamine to 16 mg/day over 4 weeks and receiving galantamine at 8 mg/day from the start to the end of the study. The study lasted 5 months for all four groups. Only patients with diagnosed Alzheimer's disease who had a score of at least 18 on the Alzheimer's Disease Assessment Scale (ADAS-cog-11) cognitive function score [Rosen, W.G. et al., Amer. J. Psychiatry, 141:1356-1364 (1984)] and whose mental decline was gradual at first and progressive over a period of at least 6 months were included in the study.

The dosing regimens for the different groups were as follows:

members of the placebo group received a placebo for 21 weeks (5 months).

Members of the group called “Gal 24” received 8 mg/day (2 x 4 mg daily) of galantamine for 4 weeks, 16 mg/day (2 x 8 mg daily) for another 4 weeks, and then 24 mg/day (2 x 12 mg daily) for 13 weeks.

Members of the group called “Gal 16” received galantamine at 8 mg/day (2 x 4 mg daily) for 4 weeks and then at 16 mg/day (2 x 8 mg daily) for 17 weeks.

Members of the “Gal 8” group received 8 mg of galantamine per day (2 x 4 mg per day) right from the start for 21 weeks.

Each patient was monitored throughout the study period, with follow-up and cognitive assessment tests performed at week 4, 3, and 5 after the start of treatment.

The primary efficacy outcome was the change from baseline in the ADAScog/11 and CIBIC-plus (Clinician’s Interview Based Impression of Change Plus Family Input) scores at month 5. These two tests, together with the Mini-Mental State Examination (MMSE) used at screening, are described below:

The ADAS consists of two parts—the cognitive and behavioral subscales. The behavioral subscale was not used. The cognitive functioning subscale, the ADAS-cog/11, which consisted of a memory test for word recall and word recognition, a test for naming objects and fingers, a test for understanding instructions, a test for editing and conceptualization, an orientation test, a memorization test, and tests for speaking ability, speaking comprehension, and difficulty finding the right words, was the primary main variable of the study.

In addition to these units of the ADAS-cog/11, we examined two additional ADAS items: the ability to concentrate and distractibility, which are actually parts of the behavioral subscale, and the delayed word recall test (delayed recall of word recall items), which provided additional information on cognitive status. This extended 13-item ADAS (ADAS-cog-13) was considered the secondary variable.

To reduce variability caused by circadian fluctuations in cognitive status, the ADAS was always performed at the same time, preferably in the morning. The test should only be performed by a person experienced in ADAS. Ideally, the person performing the ADAS was unaware of the treatment regimen used in the patient and had no access to AE (adverse event) reports.

ADAS tests were performed at visits 1, 2, 3, 4 and 5 (screening, baseline, treatment week 4, treatment week 13 and treatment month 5 or early treatment discontinuation). Two parallel word sets, “A” and “B” lists, were used for word recall and word recognition. Set “A” was used at visits 1 and 3, and set “B” was used at visits 2, 4 and 5 or early treatment discontinuation. For practical reasons, words were presented only once for word recognition. Total scores for the 11 cognitive units were recorded on the original ADAS cognitive subscale (ADAS-cog/11, range: 0-70).

The CIBIC-plus score was the second main variable. During treatment, an independent, experienced and appropriately trained clinician assessed the patient's overall condition, either worsening or improving, based on separate interviews with the patient and their caregivers. For later reference, the CIBIC assessor recorded the baseline interview on tape or videotape.

The difference from baseline was graded on a 7-point scale, with 1 indicating marked improvement, 4 indicating no change, and 7 indicating marked deterioration. CIBIC-plus assessments were performed at visits 2, 3, 4, and 5 (baseline, week 4, week 13, and month 5 or early treatment discontinuation). The test was administered by an individual experienced in CIBIC assessment.

The MMSE is a very brief cognitive screening test that includes tests of temporal and spatial orientation, momentary recall, short-term memory, and the ability to perform sequential subtraction or backward spelling, editing skills, and speech use. The MMSE score was obtained by adding the scores of the tests performed. The maximum possible score is 30. The MMSE was administered at Visit 1 (screening test).

The secondary efficacy variable was the ADAS-cog-11 and the ADCS/ADL scale. The ADCS/ADL test was performed as follows:

The ADCS/ADL scale is a 23-item, information-based rating scale that broadly measures appropriate activities of daily living in patients with mild to moderate Alzheimer's disease. The 23 items were selected from a larger series of 45 items published by Galasko et al. [Galasko et al.,: Alzheimer Disease and Associated Disorders, Vol. 11., suppl. 2. (1997)]. Each item was scored from 0-3 to 0-7, depending on the question, with a maximum possible score of 78. Higher scores indicated better patient condition. The items and scores examined were: eating (0-3); walking (0-3); toileting (0-3); washing (03); personal care (0-3); dressing: choosing clothing (0-3), physical performance while dressing (0-4); making a phone call (0-5); watching television (0-3); conversing (0-3); serving food (0-3); using personal items (0-3); obtaining drinks (0-3); preparing food or snacks (0-4); taking out the trash (0-3); traveling outside the home (0-4); shopping (0-4); showing up at an agreed place and time (0-3); ability to be alone (0-3); behaving appropriately in the situation (0-3); reading (0-2); writing (0-3); hobbies (0-3); operating household appliances (0-4).

Neuropsychiatric behavior was assessed using the NPI (The Neuropsychiatric Inventory) test [Cummings, J. L. et al., Neurology, 44: 2308-2314 (1994)]. The NPI covers 10 behavioral domains observed in people with Alzheimer's disease: delusions, hallucinations, restlessness/aggressiveness, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability/lability, and aberrant motor behavior. Abnormal behavior may be absent (0 points) or present in each domain. If abnormal behavior was present, its frequency and severity were assessed based on responses to a sub-question group on abnormal behaviors specific to that domain. Severity was rated as mild, moderate, or severe with scores ranging from 1 to 3. Frequency was rated as occasional, rare, common, or very common with scores ranging from 1 to 4. The product of the frequency and severity scores (maximum 12) were calculated for each subject area. The total NPI score was the sum of the products of frequencies and severities for each subject area (maximum 120). NPI assessments were performed at visits 2, 3, 4 and 5 (baseline, treatment week 4, treatment week 13 and treatment month 5 or time of early treatment discontinuation).

All data from the treatment groups (placebo, 8 mg/day, 16 mg/day and 24 mg/day galantamine) were compared with each other,

Comparisons between treatment groups (with particular attention to differences from placebo) were made at each dosing period and at each endpoint included in the design. Comparisons were based on differences from baseline scores for efficacy parameters with baseline (e.g., ADAS-cog/11) and on original scores for efficacy parameters without baseline (e.g., CIBIC-plus).

For continuous data, a two-way analysis of variance (ANOVA) model was used, with treatment and investigator as factors to compare changes from baseline in the treatment groups. The interaction between treatment and investigator was examined. The effect of baseline scores on the difference from baseline was assessed. If baseline scores were found to be significant (p<10), an analysis of covariance (ANCOVA) model was used to examine the effects of treatment and the interaction between treatment and baseline scores. If parametric methods were deemed inappropriate (the assumption of normality of the data was not met), nonparametric methods were used for investigator, such as two-way ANOVA on ranked data, Van Elteren test. Following ANOVA, Fisher's LSD was used to compare each galantamine group and the placebo group (pairwise). To examine the dose-response relationship on the main effect of treatment, a linear contrast procedure was used.

For ordinal categorical variables such as CIBIC-plus scores, the Van Elteren procedure was used to control for investigator bias in between-group comparisons. For nominal data (e.g., event rates), the Cochran-Mantel-Haenszel general association procedure was used to control for investigator bias. For the proportion of patients who remained unchanged or improved, a linear contrast procedure was used to examine increasing responses with increasing doses.

If a significant proportion of patients discontinued treatment prematurely, additional studies were performed to assess the effects on outcomes. In addition to the visit-based analysis, a continuous, repeated measures assessment procedure was also used to examine the effect of treatment over time.

The safety of the active substance was also monitored during the studies. At each visit and at the completion of all efficacy studies, blood samples were collected for biochemical and hematological tests, and random urine samples were also collected for urinalysis. Systolic and diastolic blood pressure were measured in the sitting position at each visit, and heart rate and other vital signs were recorded.

Patient demographics and baseline characteristics were well balanced across treatment groups (Table 1). These Alzheimer's disease patients had mild to moderate cognitive performance at baseline as measured by MMSE and ADAS-cog/11 scores (scores ranging from approximately 18 and 28 to 20).

Table 1 - Demographic and baseline characteristics

EXAMINATION DESIGN AND PATIENT CHARACTERISTICS PLACEBO GAL 8mg GAL 16 mg GAL 24 mg TOTAL NUMBER OF PATIENTS 286 140 279 273 THOSE WHO COMPLETED THE EXAM (%) 240 (84%) 108 (77%) 219 (79%) 212 (78%) PATIENTS' GENDER: MALE FEMALE 108(38%) 178(62%) 50(36%) 90(64%) 105(38%) 174(62%) 90(33%) 183(67%) AGE (YEARS): AVERAGE (SE) MEDIAN (MIN- MAX) 77.1(0.46) 78(53-100) 76.0(0.61) 77(52-91) 76.3(0.49) 77(51-94) 77.7(0.43) 78(57-95) RACE: BLACK CAUCASIAN CREOLE FAR EASTERN OTHER 13,267(93%) 3 3 0 5 132(94%) 3 0 0 12,260(93%) 5 1 1 14,249(91%) 4 3 3 MMSE TOTAL SCORE AVERAGE (SE) MEAN (MIN-MAX) 17.7(0.21) 19(10-22) 18.0(0.30) 19(10-22) 17.8(0.21) 19(10-22) 17.7(0.23) 19(10-22) ADAS-cog/11 BASELINE AVERAGE (SE) MEAN (MIN-MAX) 29.4(0.63) 27(10-61) 27.8(094) 26(1 1-62) 29.4(0.66) 28(10-62) 29.0(0.67) 27(10-54)

The number of patients randomized to the 4 groups was 978. The total number of patients who completed the study was high (approximately 80%), and discontinuation of treatment due to adverse events was relatively uniform, relatively infrequent, and evenly distributed across all treatment groups (see Table 2).

Table 2 - Test interruption

REASON FOR INTERRUPTION OF THE INVESTIGATION PLACEBO GAL 8mg GAL 16 mg GAL 24 mg TOTAL NUMBER OF PATIENTS 286 140 279 273 NUMBER OF THOSE WHO COMPLETED THE EXAM, (%) 240 (84%) 108 (77%) 219 (79%) 212 (78%) NUMBER OF THOSE WHO DROPPED THE EXAM (DC), (%) 46(16%) 32(23%) 60(22%) 61(22%) DUE TO DC SIDE EFFECT 20 (7%) 9 (6%) 19 (7%) 27 (10%) DUE TO DC INABILITY 0 1 (1%) 0 2 (1%) DC FOR OTHER ^REASONS 23 (8%) 18 (13%) 29 (10%) 20 (7%) DUE TO DC INABILITY 0 0 4 (1%) 2 (1%) DUE TO LACK OF DC COOPERATION 3 (1%) 4 (3%) 7 (3%) 10 (4%) DC DUE TO WITHDRAWAL OF CONSENT 0 0 1 (0.4%) 0

The discontinuation of the study for other reasons was mainly due to withdrawal of consent.

In this study, we obtained two primary efficacy endpoints according to commonly used international standards: change from baseline in ADAS-cog/11 scores at month 5 and change in CIBIC-plus scores at month 5.

Table 3 and Figure 1 show the statistically significant effect of galantamine 16 mg/day and 24 mg/day compared to placebo in the ADAS-cog/11. The results from the analysis based on the last observation carried-forward (LOCF) data confirmed the results based on the observed data. The galantamine 8 mg/day group was significantly different from the placebo group in the observed cases, but not in the LOCF. Galantamine 24 mg/day did not appear to be significantly more effective than 16 mg/day. However, the time to reach the final dose differed by 1 month between the two groups (2 months versus 3 months).

Table 3 - Difference from baseline in ADAS-cog/11 at month 5

PLACEBO GAL 8 mg GAL 16 mg GAL 24 mg MONTH 5:(OBSERVED CASES) n = 225 n = 101 n = 208 n = 211 AVERAGE (SE) 1.8(0.43) 0.1(0.58)* -1.5(0.40)**** -1.8(0.44)**** MONTH 5: (LOCF) n = 255 n = 126 n = 253 N = 253 AVERAGE (SE) 1.7(0.39) 0.4(0.52)¼ -1.4(0.35)**** -1.4(0.39)*** *

A lower score indicates a better result. P-values are based on the two-way ANOVA model.

the markings:

significantly more effective than placebo: *p< 0.05; **p< 0.01;

*** p < 0.001 approximate significance: ♦ 0.05< p-value < 0.10 significantly more effective than 8 mg/day dosing:

*p<0.05; *p<0.01.

In the CIBIC-plus assessment, the percentage of patients with improved or unchanged scores at month 5 was significantly higher in the galantamine 16 mg/day and 24 mg/day groups than in those receiving placebo or galantamine 8 mg/day (see Table 4). After five months of treatment, 64% to 68% of patients receiving galantamine 16 mg/day and 24 mg/day, respectively, had improved or remained unchanged from baseline, compared with only 47% to 51% of patients receiving placebo or galantamine 8 mg/day. Analysis of data imputed at the LOCF endpoint yielded similar results. A clear dose-dependent increase in the percentage of patients with improved or unchanged scores was found on the CIBIC-plus scale ( Figure 2 ).

Table 4 - CIBIC-plus scores showing improvement or no change at month 5

PLACEBO GAL 8 mg GAL 16 mg GAL 24 mg MONTH 5: (OBSERVED CASES) n=237 n = 106 n = 212 n = 212 IMPROVED/UNCHANGED 112 54 143 136 STATE, (%) (47%) (51%) (68%)*** ⁺ (64%)**** MONTH 5: (LOCF) n = 263 n = 128 n = 255 n = 253 IMPROVED/UNCHANGED 128 68 169 162 STATE, (%) (4 9%) (53%) (66%)*" ⁺ (64%)*** *

The p-values are according to the Van Elteren 7-point scale.

the markings:

significantly more effective than placebo: *p < 0.05; **p 0.01;

*** p < 0.001 significantly more effective than 8 mg/day: ⁺ p < 0.05, * p < 0.01.

At month 5, significantly more patients remained stable or improved with galantamine 16 mg/day and 24 mg/day compared with placebo or galantamine 8 mg/day. The percentage of patients who showed a 7 or more point difference from baseline on the ADAScog/11 scale was 15.9% and 22.3% in the 16 mg/day and 24 mg/day groups, respectively, compared with placebo (7.6%). Overall, the cumulative percentage of patients who showed any minimal improvement with galantamine was higher than with placebo (Figure 3).

Table 5 - Analysis of patients responding to treatment by

Change from baseline on ADAS-cog/11 scale>

based on the 5th month

DETERMINING RESPONDERS PLACEBO GAL 8 mg GAL 16 mg GAL 24 mg n = 225 n = 101 N = 208 n = 21 1 CHANGE <POINT N, (%) 94 (41.8) 47 (46.5) 136(65.4)*** * 137(64.9 )*** ^T CHANGE <4POINTS N ,(%) 44 (19.6) 26 (25.7) 74 (35.6)*** ♦ 78 (37.0)*** ⁺ CHANGE <7POINTS N, (%) 17 (7.6) 14 (13.9) 33 (15.9)** 47 (22.3)*** CHANGE<10POINTS N, (%) 8 (3.6) 6 (5.9) 15 (7.2) 22 (10.4)**

The p-values are based on the CMH procedure.

Significantly higher percentage of responders compared to placebo: *p < 0.05; **p < 0.01; ***p < 0.001 Significantly higher percentage of responders compared to those taking 8 mg/day galantamine: + p < 0.05; *p < 0.01; approximate significance: ♦ 0.05< p-value < 0.10 approximate significance difference between 16 mg/day and 24 mg/day:^ 0.05< p-value < 0.10.

An additional secondary indication included overall performance changes in activities of daily living (ADL), as measured by the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS/ADL) Scale. As previously mentioned, this is a 23-item scale that has been tested and validated in patients with mild to moderate Alzheimer's disease.

Galantamine treatment at 16 mg/day and 24 mg/day for 5 months was statistically significantly more effective in maintaining total ADL scores at baseline than placebo or galantamine 8 mg/day (Table 6). The dose-dependent effect of galantamine treatment is clearly visible in Figure 4, which shows the change in total ADL scores over time.

Table 6 - Change from baseline in total ADL score at month 5

PLACEBO GAL 8 mg GAL 16 mg GAL 24 mg 5.MONTH;(OBSERVED CASES) N = 235 n = 106 n = 212 n = 212 ATLAG (SE) -4.0(0.59) -3.1(0.91) -0.5(0.55)*** ⁺ -1.6(0.61)** MONTH 5: (LOCF) N = 262 n = 129 n = 255 n = 253 AVERAGE (SE) The low vahb -3.8(0.55) η η n f ς 7 á m in -3.2(0.79) hh -0.7(0.05)**** -1.5(0.56)**

are based on a one-way ANOVA model.

Significantly more effective than 0.001 approximate significance: ♦ 0.05< significantly more effective, ⁺ p <0.05; * p < 0.01.

placebo:** p<0.01;

p-value <0.10 compared to 8 mg/day dosing:

There was a statistically significant improvement (p<0.05) in the change from baseline in the total NPI score at month 5 in patients treated with galantamine 16 mg/day and 24 mg/day, compared with a worsening in patients treated with placebo and galantamine 8 mg/day (Table 7 and Figure 5). An increase in score indicates a worsening of the condition. Thus, we observed a preservation of neuropsychiatric behavior with galantamine 16 mg/day and 24 mg/day.

Table 7 - Change from baseline in total NPI score at month 5

PLACEBO GAL 8 mg GAL 1 6 mg GAL 24 mg MONTH 5:(OBSERVED CASES) n = 234 n = 106 n = 211 n = 212 AVERAGE (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 AVERAGE (SE) 2.0 (0.68) 2.3 (1.00) -0.1(0.71)* -0.0(0.76)*

Higher scores indicate worse condition. P-values are based on two-way ANOVA.

significantly more effective than placebo:* p< 0.05.

The most common adverse reactions were evenly distributed across the study groups, except for events that were thought to be related to cholinomimetics (Table 8). Among the treatment-related symptoms, nausea, vomiting, and anorexia showed a mild dose-dependence with a relatively low incidence.

Table 8 - Frequency of most common adverse reactions (>5%) in proportion to the number of patients (%)

SIDE EFFECT (GENERIC NAME) PLACEBO GAL 8 mg GAL 16 mg GAL 24 mg TOTAL NUMBER OF PATIENTS 286 140 279 273 NAUSEA 13 (4.5%) 8 (5.7%) 37 (13.3%) 45 (16.5%) VOMIT 4 (1.4%) 5 (3.6%) 17 (6.1%) 27 (9.9%) LACK OF APPETITE 9 (3.1%) 8 (5.7%) 18 (6.5%) 24 (8.8%) RESTAURANCE 27 (9.4%) 21 (15.0%) 28 (10.0%) 22 (8.1%) DEPRESSION 15 (5.2%) 4 (2.9%) 24 (8.6%) 22 (8.0%) Vaginal Infection 19 (6.6%) 11 (7.9%) 23 (8.2%) 22 (8.1%) DIZZINESS 10 (3.5%) 7 (5.0%) 15 (5.4%) 19 (7.0%) INJURY 12 (4.2%) 5 (3.6%) 12 (4.3%) 16 (5.9%) DIARRHEA 17 (5.9%) 7 (5.0%) 34 (12.2%) 15 (5.5%) DIGESTIVE DISORDER 7 (2.4%) 4 (2.9%) 13 (4.7%) 15 (5.5%) HEADHAEK 13 (4.5%) 5 (3.6%) 19 (6.8%) 13 (4.8%) WEIGHT REDUCTION- LUBRICATION 4 (1.4%) 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 (2.9%) 11 (4.0%) PERIPHERAL EDEMA 7 (2.4%) 9 (6.4%) 8 (2.9%) 7 (2.6%)

There was no difference or a very slight dose-related effect between the treatment groups for clinically relevant adverse events (Table 9). The incidence of bradycardia was higher in patients treated with galantamine than in patients treated with placebo, but no detectable dose-related effect was found. For syncope, there was a slight dose-related increase in the incidence of syncope in the 24 mg/day group, but 3 cases occurred during the titration period, i.e. at a lower dose, and are therefore attributable to the lower dose. Consequently, the incidence shown in Table 9 is likely to overestimate the incidence of syncope at higher doses. Furthermore, of the 18 patients who experienced syncope, 10 patients were receiving cardiovascular medication in addition to galantamine treatment, including beta-blockers, calcium channel blockers, ACE inhibitors and/or diuretics. Of these 18 patients, 11 had active cardiovascular disease as documented in their medical history. Thus, the majority of patients who experienced syncope either had cardiovascular disease or were receiving cardiovascular medication.

Table 9 - Clinically significant adverse reactions

SIDE EFFECT (GENERIC NAME) PLACEBO GAL 8 mg GAL 16 mg GAL 24 mg TOTAL NUMBER OF PATIENTS 286 140 279 273 BRADYCARDIA 1 (0.3%) 5 (3.6%) 7 (2.5%) 8 (2.9%) CRAMPS 2(0.7%) 0 (0.0%) 0 (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 between treatment groups and (with the exception of syncope) did not show a dose-related relationship (Table 10). The four most common serious adverse events of galantamine, occurring at a frequency of at least 1% in any group, were injury, syncope, fall and myocardial infarction. There was no dose-related increase in serious gastrointestinal adverse events. The only serious adverse event that showed a dose-related relationship was syncope, but for the reasons already mentioned, its significance may be overestimated.

Table 10-Serious adverse reactions (2 patients/group)

SIDE EFFECT (GENERIC NAME) PLACEBO GAL 8 mg GAL 16 mg GAL 24 mg TOTAL NUMBER OF PATIENTS 286 140 279 273 TOTAL NUMBER OF PATIENTS WHO EXPERIENCED SERIOUS SIDE EFFECTS 31(10.8%) 14(10.0%) 28(10.1%) 35(12.8%) INJURY 4 (1.4%) 1 (0.7%) 1 (0.4%) 5 (1.8%) SYNCOPE 2 (0.7%) 1 (0.7%) 4 (1.4%) 5 (1.8%) ASTENIYA 1 (0.3%) 0 (0.0%) 2 (0.7%) 1 (0.4%) DIGESTIVE DISORDER 1 (0.3%) 0 (0.0%) 2 (0.7%) 3 (1.1%) Pneumonitis 4 (1.4%) 1 (0.7%) 2 (0.7%) 3 (1.1%) GASTROINTESTINAL BLEEMORRHAGE 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (0.7%)

VOMIT 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 1 (0.3%) 0 (0.0%) 2 (0.7%) 0 (0.0%) BASAL CELL CANCER 0 (0.0%) 0 (0.0%) 0 (0.0%) 2 (0.7%) BREAST NEOPLASM (FEMALE) 2 (0.7%) 0 (0.0%) 0 (0.0%) 0 (0.0%) FALL 3 (1.0%) 4 (2.9%) 1 (0.4%) 3 (1.1%) SURGERY 1 (0.3%) 0 (0.0%) 3 (1.1%) 0 (0.0%) DEEP VEIN THROMBOPHLEBITIS 1 (0.3%) 0 (0.0%) 0 (0.0%) 2 (0.7%) TRANSIENT ISCHEMIC ATTACK 1 (0.3%) 1 (0.7%) 2 (0.7%) 0 (0.0%) MYOCARDIAL INFARCTION 2 (0.7%) 3 (2.1%) 1 (0.4%) 1 (0.4%) EXCITION 1 (0.3%) 2 (1.4%) 1 (0.4%) 0 (0.0%) Vaginal Infection 0 (0.0%) 1 (0.7%) 2 (0.7%) 0 (0.0%) HEARTLESSNESS 2 (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 2 (0.7%) 0 (0.0%) 0(0.0%) 0 (0.0%)

Eleven patients died during the study. No clear dose-related relationship was found for the deaths. According to the investigator, none of the deaths were related to the drug trial.

The results of the exemplary study confirmed that both 16 mg/day and 24 mg/day galantamine resulted in statistically significant improvements in neuropsychiatric behaviors, as measured by NPI scores from baseline at month 5 of treatment, compared with the worsening observed with placebo or 8 mg/day galantamine.

All scientific publications and patents are incorporated by reference into this invention.

The present invention has been described with reference to preferred embodiments. However, it will be apparent to those skilled in the art that numerous changes and modifications can be made within the scope of the invention as set forth in the following claims.

Claims (11)

PATENT CLAIMS 1. Use of an effective amount of galantamine or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for the treatment of neuropsychiatric behaviors associated with Alzheimer's disease. 2. The use according to claim 1, wherein the daily dosage of galantamine is from about 1 mg to about 100 mg. 3. The use according to claim 2, wherein the daily dosage of galantamine is from about 5 mg to about 50 mg. 4. The use of claim 3, wherein the daily dosage of galantamine is from about 16 mg to about 32 mg. 5. The use of claim 4, wherein the dosage of galantamine is about 24 mg/day, which dosage can be achieved by a stepwise increase in dosage, whereby about 8 mg/day is administered for about 1 week, then about 16 mg/day for about 1 week, and then about 24 mg/day of galantamine thereafter. 6. The use of claim 4, wherein the galantamine dosage is about 32 mg/day, which dosage can be achieved by a stepwise dose escalation, whereby about 8 mg/day for about 1 week, then about 16 mg/day for about 1 week, then about 24 mg/day for about 1 week, and then about 32 mg/day of galantamine. 7. The use of claim 4, wherein the dosage of galantamine ranges from about 16 mg to about 24 mg, which dose is achieved by a gradual dose increase over a period of about 2 weeks to about 10 weeks, increasing the dose from an initial dose of about 8 mg/day to a final dose of about 16 mg to about 24 mg. 8. The use of claim 7, wherein the galantamine dosage is about 24 mg/day, which dosage can be achieved by a stepwise increase in dosage, whereby about 8 mg/day is administered for about 2 to about 4 weeks, then about 16 mg/day for about 2 to about 4 weeks, and then about 24 mg/day of galantamine thereafter. 9. The use of claim 7, wherein the galantamine dosage is about 24 mg/day, which dosage can be achieved by a stepwise dose escalation, whereby about 8 mg/day for about 4 weeks, then about 16 mg/day for about 4 weeks, and then about 24 mg/day of galantamine thereafter. 10. The use of claim 4, wherein the dosage of galantamine is about 16 mg/day, which dosage can be achieved by a stepwise dose escalation, whereby about 8 mg/day of galantamine is administered for about 2 to about 4 weeks, and then about 16 mg/day thereafter. 11. The use of claim 9, wherein the dosage of galantamine is about 16 mg/day, which dosage can be achieved by a stepwise dose escalation, whereby about 8 mg/day of galantamine is administered for about 4 weeks, followed by about 16 mg/day thereafter. The authorized representative: DANUBIA Patent and Trademark Office Ltd. Dr. Ildikó Kiss Patent Attorney ‘T > · c-5- Our file number: 97421-3689 Sl