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Long-Term Effects of Rivastigmine Treatment on Neuropsychiatric and Behavioral Disturbances in Nursing Home Residents With Moderate to Severe Alzheimer's Disease: Results of a 52-Week Open-Label Study

Posted on: Saturday, 18 December 2004, 03:00 CST

Key words: Alzheimer's disease - Behavioral disturbances - Cholinestcrasc inhibitor Neuropsychiatric symptoms - Rivastigmine

SUMMARY

Objectives: To evaluate the safety and efficacy of longterm treatment with rivastigmine (3-12 mg/day) and its effects on neuropsychiatrie and behavioral disturbances in nursing home patients with moderate to severe probable Alzheimer's disease (AO).

Methods: h prospective, multicenter 26-week openlabel extension to a 26-week open-label study (52 week results) of rivastigmine treatment in patients with Mini-Mental State Examination (MMSE) scores of 6-15 inclusive, residing in nursing homes at 13 centers in the US. Effects of treatment with rivastigmine for up to 52 weeks on neuropsychiatrie and behavioral symptoms were examined using the Neuropsychiatrie Inventory-Nursing Home (NPI-NH) scale. Cognitive function was assessed by the MMSE, and the Naming Objects and Fingers Test (NOFT) subset of the Alzheimer's Disease Assessment Scale - Cognitive subscale (ADAS-Cog). Global functioning was assessed using the simplified Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus).

Results: Rivastigmine (3-12 mg/day) significantly improved neuropsychiatrie and behavioral symptoms compared to baseline (in patients with specific behavioral disturbances at baseline) in observed cases (OC) and last observation carried forward (LOCF) analyses. Over 52 weeks, treatment with rivastigmine significantly improved 10 of 12 individual NPI-NH domains from baseline in LOCF patients with symptoms present at baseline. Cognitive function was stable, indicated by the lack of decline in MMSE and the NOFT. Global function was stabilized or improved in greater than half of the patients as indicated by the simplified CIBIC-Plus scores.

Conclusion: Rivastigmine showed potential benefit in the long- term treatment of behavioral symptoms as well as cognitive and global functioning in nursing home residents with moderate to severe AD with concurrent behavioral symptoms present at baseline. Although these results suggest that treatment with rivastigmine may have beneficial behavioral effects and cognitive benefits on patients with moderate to severe AD, they are subject to the limitations of an open-label study.

Introduction

Alzheimer's disease (AD) is a progressive neurodegenerative disorder that affects more than 4 million Americans'. Researchers predict that as the median age of the US population increases, this number will increase almost 3-fold to 13.2 million by 20502. Data from the 1999 National Nursing Home Survey indicate that 231,900 nursing home residents (14.2%] were diagnosed with AD3.

AD is associated with behavioral disturbances in up to 90% of patients4. Behavioral disturbances cause patient distress, exacerbation of disability, increased burden on

the caregiver, and may precipitate the need to institutionalize patients5. In addition, the proportion of patients who experience behavioral symptoms increases with severity of the disease6. Neuropsychiatrie manifestations of the disorder include apathy, agitation, depression, irritability, aberrant motor behaviors (pacing, rummaging, wandering), delusions, and hallucinations5.

The Cache County Study of Memory in Aging of 5092 elderly residents (mean age = 84.4 years) showed that 60% of individuals with AD reported at least 1 neuropsychiatrie symptom. The most common symptoms included apathy in 27.3%, delusions in 22.7%, and agitation in 20.7% of patients7.

Rivastigmine (Exelon*) is a slowly reversible cholinesterase inhibitor of the carbamate type with high affinity for both acetyl- and butyrylcholinesterase (AChE and BuChE). In contrast to other available agents, rivastigmine demonstrates regional selectivity for the hippocampus and cortex8 and is the only widely prescribed agent with the ability to inhibit BuChE.

In two double-blind, placebo-controlled trials, rivastigmine significantly improved cognitive performance, global functioning, and activities of daily living in patients with mild to moderate AD'"0. In another analysis of three pooled placebo-controlled phase III clinical trials of patients with severe AD, 26 weeks of treatment with rivastigmine, 6-12 mg/day, was associated with significant improvements in cognition, activities of daily living, and behavioral symptoms". In a randomized, placebo-controlled trial, rivastigmine also has been shown to improve behaviors in dementia with Lewy bodies (DLB), an AD-related condition in which behaviors are generally more severely disturbed than in AD12.

This 26-week extension to a 26-week open-label study was conducted to further evaluate the long-term safety and efficacy of rivastigmine in patients with moderate to severe probable AD residing in a long-term care setting. The primary efficacy variable used in the study was change from baseline in total score of the Neuropsychiatrie Inventory-Nursing Home (NPI-NH); effects of rivastigmine on cognitive performance and global functioning of these patients were secondary efficacy outcome measures. The safety and tolerability of treatment with rivastigmine in this patient population also were evaluated. This paper presents 52-week data, whereas 26-week data from this study is the topic of another publication13.

Patients and methods

Study Design

The 26-week open-label prospective extension to a 26-week study included patients from 13 centers, including 29 US nursing homes. Patients with moderate to severe AD were treated with escalating doses of rivastigmine taken twice daily (3-12mg/day).

Patients

Men and postmenopausal women aged 50years or older residing in nursing homes were eligible to participate. Study participants satisfied National Institute for Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association (NINCDS/ADRDA) criteria for a clinical diagnosis of probable AD14, as well as the Diagnostic and Statistical Manual, edition 4 (DSM-IV) criteria for dementia of the Alzheimer's type. Patients who were enrolled also had moderate to severe AD with a total and inclusive Mini Mental State Examination (MMSE) score between 6 and 15. Individuals with concurrent, stable medical conditions or who were receiving concomitant psychotropic medications, including anxiolytics, hypnotic sedatives, antipsychotics, antidepressants, and mood stabilizers were eligible to participate.

Patients presenting with advanced, severe, and/or unstable diseases (other than AD) that could either interfere with protocol- defined primary and secondary efficacy outcomes and safety evaluations or that may increase risk to the patient were excluded. On a case-by-case basis, however, the medical monitor may have approved the inclusion of patients outside these ranges, provided there was a clear rationale for inclusion based on the clinical judgment of the principal investigator. Patients with dementia unrelated to AD, according to computed tomography, magnetic resonance imaging, and/ or other clinical studies also were excluded. Hypersensitivity to rivastigmine or other cholinesterase inhibitors disqualified patients, as did any ongoing concomitant regimens (i.e., other AChEIs) or food supplements that were acetylcholine precursors or memory enhancers.

The study was conducted in accordance with Good Clinical Practice and ethical principles of the Declaration of Helsinki. Local institutional review boards approved the informed consent document, protocol, and amendments. Both patients and their caregivers gave written informed consent prior to study entry if the patient was mentally competent. If the patient was unable to provide written informed consent, written consent was obtained from someone responsible for the patient and verbal assent was obtained from the patient if possible and permitted by state, local, and internal review board regulations.

Treatment with Rivastigmine

Patients began open-label treatment with rivastigmine 1.5mg BID. After one or two weeks, patients received escalating doses in increments of 1.5mg BID for one to two weeks, based on tolerability, until they reached their maximum tolerated dose, not to exceed 6 mg BID. Reductions in dose were permitted at any time during the study.

Outcome Measurements

Four instruments were used to assess the effects of rivastigmine on behavior, cognitive performance, and global functioning; the primary outcome variable was the NPI-NH scale to assess behavioral disturbances15. The MMSE and the Naming Objects and Fingers Test (NOFT) of the Alzheimer's Disease Assessment ScaleCognitive subscale (ADAS-Cog) assessed cognitive function, and the simplified Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBICPlus)16,17 assessed patients' global function. Efficacy data presented in this paper are derived from the following time points:

* MMSE: Screening, baseline and Week 52

* NPI-NH: Screening, baseline, and Week 52

* Simplified CIBIC-Plus: An interview was performed at baseline and a rating of change from baseline was performed at Week 52, or premature discontinuation (to avoid bias, this evaluation was conducted prior to any other efficacy evaluations)

Raters were trained in data \collection using standardized scripted instruments and all data were collected on standard case report forms.

NPI-NH

A valid and reliable interview-based assessment of the frequency and severity of behavioral symptoms in patients with dementia, the NPI-NH scale includes 12 behavioral domains: delusions, agitation, depression, anxiety, euphoria, elation, apathy/indifference, disinhibition, irritability/lability, aberrant motor behavior, appetite/eating changes, and nighttime behaviors. Trained staff caregivers who were familiar with the patient's behavior conducted the NPI-NH. The NPI-NH was performed at sceening, baseline and at Weeks 12, 26, and 52.

Frequency and severity were evaluated for each symptom. In the absence of a symptom, a score of zero was assigned for frequency and severity. Frequency scores ranged from one (occasionally, less than once weekly) to four (very frequently, daily or continuously). Severity scores ranged from one (mild, producing little distress) to three (severe, very disturbing). The score on each symptom domain was the product of each score for severity and frequency (maximum = 12). The total score is obtained by adding the scores for the individual 12-symptom domains (maximum score of 144).

MMSE

The MMSE is a brief, practical screening test for cognitive dysfunction comprised of five sections (orientation, registration, attention-calculation, recall, and language) and results in a total possible score of 30 for individuals without cognitive impairment. The MMSE was used to assess cognitive performance during the study and was completed at screening, baseline, and at Weeks 12, 26, 39, and 52. The MMSE score at baseline was used to categorize patients as having moderate (MMSE ≥ 10) or severe (MMSE < 10) cognitive impairment.

ADAS-COG NOFT

The ADAS-Cog is a performance based test that measures specific cognitive dysfunctions in patients with AD18. The NOFT, a scale from the ADAS-Cog, was used to assess cognition. This test consisted of 17 items and is scored based on the total number of items named incorrectly. Possible scores range from zero to five with increasing scores associated with more revere impairment. The NOFT was performed at screening, baseline, and at Weeks 12, 26, and 52.

Simplified CIBIC-Plus

The seven point interview-based CIBIC-Plus was used to evaluate the change from baseline in global function. This simplified rating scale includes subjective assessments of cognitive impairment, behavioral disturbances, and functional status. A score of one signifies marked improvement from baseline, four denotes no change, and seven represents marked worsening. Caregivers were also interviewed separately to obtain information concerning changes in the patient's condition. The interview was performed at baseline and at Weeks 26 and 52.

Safety

Safety and tolerability evaluations, which included vital signs and adverse events, were performed every two weeks during titration and at the end of Weeks 4, 12, 26, 39, and 52. Adverse event monitoring was performed as required throughout the study. Electrocardiograms (ECGs) were performed at screening and at the end of Weeks 12, 26, and 52; physical examinations were performed at screening and at the end of Weeks 26 and 52; and laboratory evaluations (hematology and blood chemistries) were performed at screening and at the end of Weeks 4, 12, 26, and 52. Adverse events were classified using a World Health Organization (WHO)-based dictionary of preferred terms from the modified Sandoz Medical Terminology Thesaurus. In this paper, only adverse events with a frequency ≥ 10% are presented.

Analyses

The efficacy analyses for this report consider both the observed cases (OC) analysis (patients with at least one evaluation while on study medication at the designated assessment times) and a modified intent-to-treat population, with the last-observation-carricd- forward (LOCF) imputation method applied to the missing data for comparison. This is referred to as the LOCF analysis and includes data from the previous visit to be carried forward to replace data from missed visits. The safety analyses included data from each patient who received at least one dose of study medication.

The primary efficacy variable was the NPI-NH (12itcm total score) change from baseline at Week 52. The 12-item total score was obtained by adding the scores (frequency x severity) of the individual subscales for the 12 symptom domains.

An analysis of the data included the proportion of patients who demonstrated a 30% or greater improvement in the NPI-NH total score after treatment with rivastigmine. The proportion of patients who had at least one neuropsychiatrie symptom at baseline and who experienced at least a 30% improvement in NPI-NH total score with rivastigmine therapy was determined, and the mean changes from baseline of the patients who exhibited each specific symptom at baseline were calculated. A 30% improvement (reduction) in NPI-NH total score was considered clinically meaningful because it represents the degree of efficacy in treating behavioral disturbances with psychotropic medications19. For the NPI-NH and the MMSE scores, a paired t-test was used to analyze changes from the baseline score. All statistical tests were conducted against a 2- sided alternative hypothesis using a significance level of 0.05. No adjustment for multiple comparisons was deemed necessary as there is only one primary endpoint in the analysis, and other comparisons are secondary.

Results

Study Population

Baseline

The mean age of patients was 82.6 5.9 years. The mean duration of dementia was 5.5 2.8 years (Table 1). There was considerable co- morbidity, with all patients reporting at least one concurrent medical condition and taking at least one concomitant medication at baseline. One hundred and fifty patients were taking psychotropic medications including anxiolytics, hypnotic sedatives, antipsychotics, antidepressants, and mood stabilizers, at some time during the trial. Based on medical histories, a total of 83.2% of patients had one or more behavioral disturbances at baseline, including agitation in 91 patients (52.6%), depression in 78 patients (45.1%), anxiety in 33 patients (19.1%), aggressive reactions in 18 patients (10.4%), delusions in 17 patients (9.8%), and hallucinations in 12 patients (6.9%).

Patient Disposition

Seventy-two (41.6%) patients completed 52 weeks of treatment and provided measurements for all efficacy variables. Reasons for discontinuation over this 26-week open-label extension (Weeks 27- 52) included withdrawal of consent (n = 6); death (n = 6); adverse events (n = 4); treatment failure (n = 3); protocol violation (n = 1); and other (n = 4) (Table 2).

Outcome Measurements

NPI-NH

At 52 weeks, statistically significant improvements from baseline were observed for 10 of the 12 individual NPI-NH domains among patients with symptoms present at baseline (LOCF analysis), including delusions, hallucinations, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability/lability, aberrant motor behaviors, nighttime behaviors, and appetite/eating changes (Tables 3, 4).

In the OC analysis, 8 of 12 NPI-NH domains were significantly improved from baseline at Week 52 in patients with symptoms present at baseline (Figure 1). Individual symptoms showing the most marked benefits compared with baseline over 52 weeks in patients with symptoms at baseline included disinhibition, nighttime behavior, hallucinations, and delusions (Figure 1).

In patients with symptoms present at baseline in the OC analysis, 50% demonstrated a clinically meaningful reduction of at least ≥ 30% in collective neuropsychiatrie and behavioral symptoms. Results for the LOCF analysis were similar (Table 4).

MMSE

The baseline MMSE score for all enrolled patients was 9.3 5.3 (Table 1). No significant decline from baseline in MMSE was observed at Week 52 in either the OC or LOCF analyses, suggesting a stabilized cognitive function in patients receiving long-term rivastigmine treatment (Table 5).

Table 1. Patient demographics and characteristics at Baseline

Table 2. Patient disposition

ADAS-Cog (NOFT)

There was no significant decline from baseline in the ADAS-Cog NOFT in either the OC or LOCF analyses. This suggests stabilization in cognitive function in patients receiving long term rivastigmine treatment as indicated by mean change scores from baseline of 0.3, and 0.2 (respectively) at Week 52.

Simplified CIBIC-Plus

Based on the 52-week data, 57.2% of the OC and 56.9% LOCF analyses showed improved or stable global function, indicated by scores of 1-4 at Week 52.

Safety

From Week 27 to Week 52, 94.7% of patients experienced at least 1 treatment-emergent adverse event (Table 6). The majority of events were mild or moderate in severity and considered unrelated to treatment with rivastigmine. Only four patients discontinued treatment due to treatment-emergent adverse events. No clinically significant study drug-related changes in vital signs or ECGs were observed in the study. Serious adverse events were reported in 17.9% of patients in Weeks 27-52. The most commonly occurring serious adverse events were pneumonia and sepsis.

Discussion

This study evaluated potential effects of rivastigmine on neuropsychiatric symptoms associated with AD in a highly co-morbid nursing home population, including patients who had an average 5- year history of AD at study entry. Results suggest that treatment with rivastigmine may be associated with benefits on neuropsychiatric and behavioral symptoms in patients with moderate to severe AD. In addition, cognition and global function were largely stable in this patient population, and long-term treatment with rivastigmine was considered safe.

Significant improvement from baseline in the majority of NPI-NH domains (in patients with symptoms present at baseline) was evident at Week 52. Improvement in specific \neuropsychiatric symptoms following administration of rivastigmine may reflect augmentation of cholinergic transmission in brain regions where a cholinergic deficiency may contribute to the development of behavioral disturbances. The cholinergic deficit is distributed throughout the brain of a patient with AD, and pathophysiological changes are marked in regions such as the frontal and temporal cortices, which are relevant to behavior20. Evidence supports the hypothesis that cholinergic deficiencies in these brain regions contribute to a broad range of observed neuropsychiatrie disturbances, including changes in personality (i.e., apathy, irritability), psychosis, aberrant motor behavior, and sleep disturbances20.

Table 3. NPI-NH total and individual domain scores for last observation carried forward population at Week 52 and mean change from baseline [patients with specific symptoms present at baseline)

Table 4. Percentage of patients with improvement from baseline in total NPl-NH score (patients with symptoms present at baseline)

Figure 1. NPI-NH total and individual domain scores for observed cases at Week 52 and mean change from baseline (patients with specific symptoms present at baseline)

Rivastigmine is the only widely prescribed treatment available that inhibits both AChE and BuChE. Results of this trial are consistent with other AChE inhibitors that have improved or suggested benefit in disturbed behaviors20. The additional ability of rivastigmine to inhibit BuChE, however, may be associated with additional clinical benefits. Increased BuChE in the inferotemporal cortex may exacerbate a local cholinergic deficit and be relevant to mediation of behavioral disturbances in AD19. Studies show perfusion of medial temporal or orbitofrontal and medial frontal cortical regions, which comprise part of the limbic system, are increased after treatment with rivastigmine.21 This increase may reflect enhanced function in these areas.

Table 5. Outcome measures: mean scores and changes from baseline (all patients)

Table 6. Treatment-emergent adverse events occurring in ≥ 10% of all treated patients

The significant benefits on neuropsychiatrie symptoms observed in the present trial suggest that treatment with rivastigmine may have long-term benefits in patients with more severe disease than has been previously reported.

During the study, the lack of decline in MMSE scores together with stabilization or improvement in the simplified CIBIC-Plus in greater than half of the patients suggests that long-term treatment with rivastigmine may provide stabilized cognition and global function even in more severely demented individuals. In the study, approximately 83.2% of patients had at least one behavioral or psychological symptom prior to baseline. Interventions that improve or maintain cognitive and behavioral function might delay nursing home placement and help patients maintain their quality of life in the community.

The use of concomitant psychotropic medications during the study period was also monitored. Most patients were taking these medications prior to the study, making it unlikely that improvements in behavioral symptoms could be attributed to the psychotropic medications. Furthermore, a decrease in the use of antipsychotics concomitant medications was seen in this patient population22.

Although many patients experienced treatmentemergent adverse events, the majority of patients were able to continue treatment with no dose adjustment. Treatment-emergent adverse events were generally mild to moderate in intensity, transient, and mostly unrelated to study medication.

Limitations

Several limitations must be considered when interpreting findings of this study: first, the open-label design of the trial with no control group makes it difficult to attribute beneficial effects to active treatment with rivastigmine; second, the attrition rate also was high and patients remaining in the study at Week 52 might represent a biased sample of enhanced responders. In addition, because no adjustment was made for multiple comparisons, the possibility of type I error cannot be ruled out, particularly with regard to the multiple analyses of the NPI-NH data. Use of the LOCF analysis is another study limitation. Although this method is commonly used in psychiatric clinical trials to accommodate missing data, the impact on the results depends on the amount of missing data and the proximity of dropout to trial end.

Conclusions

This open-label extension trial suggests that rivastigmine therapy may be associated with clinical benefits to patients with diverse neuropsychiatrie and behavioral manifestations of moderate to severe AD. Rivastigmine was tolerated in a highly co-morbid long- term care population taking numerous medications for concomitant illnesses, including psychiatric disorders. Given the relative scarcity of effective and well-tolerated treatment options for these patients, the behavioral efficacy of rivastigmine should be further evaluated in adequately powered randomized placebo-controlled trials involving patients with moderate to severe AD in the long-term care setting.

Acknowledgment

Dr. Aupperle is a consultant for and has received research grants from Novartis Pharmaceuticals, as well as editorial support from Thomson Gardiner-Caldwell US.

* Exelon is a registered tradename of Novartis Pharmaceuticals

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20. Levy ML, Cummings JL, Kahn-Rose R. Neuropsychiatric symptoms and cholinergic therapy for Alzheimer's disease. Gerontology 1999;45(Suppl 1): 15-22

21. Potkin SG, Anand R, Fleming K, Alva G, Keator D, Carreon D, et al. Brain metabolic and clinical effects of rivastigmine in Alzheimer's disease. Int J Neuropsychopharmacol 2001;4: 223-230

22. Edwards K, Mirski D, Koumaras B, Gunay I Rivastigmine Reduces Need For Antipsychotics and Other Psychotropic Medications in Nursing Home Patients with Alzheimer's Disease (manuscript in progress)

CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2578, Accepted for publication: 06 May 2004

Published Online: 26 August 2004

doi: 10.1185/030079904125004204

Peter M. Aupperle1, Barbara Koumaras2, Michael Chen2, Adrian Rabinowicz2 and Dario Mirski2

1 Division of Geriatric Psychiatry, Robert Wood Johnson Medical School, Univers\ity of Medicine and Dentistry of New Jersey, Piscataway, NJ, USA

2 Novartis Pharmaceutical Corporation, Neuroscience, East Hanover, NJ, USA

Address for correspondence: Dr Peter Aupperle, University Behavioral HealthCare, 667 Hoes Lane, Piscataway, NJ 08855-1392, USA. email: auppcrpm@umdnj.edu

Copyright Librapharm Oct 2004

Source: Current Medical Research and Opinion

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