A Study of Galantamine Used to Treat Patients With Mild to Moderate Alzheimer's Disease

Study Overview
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Brief Summary
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The purpose of this study is to compare the effectiveness and safety of 2 years of treatment with galantamine as compared with placebo of patients who have mild to moderately severe Alzheimer's disease (AD).

Detailed Description
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This is a long-term (2-year), randomized (patients will be assigned to treatment by chance), double blind (neither the physician nor the patient will know which treatment is assigned) study of galantamine versus placebo in subjects with mild to moderately-severe AD. Approximately 2,000 patients will participate in this study. The study length for each patient is approximately 25.5 months. The study consists of 3 phases: a pretreatment phase, a treatment phase, and a posttreatment phase. The pretreatment phase includes a 2-week screening period (to obtain a patient's and his or her caregiver's informed consent and to confirm eligibility for the study) and a baseline visit at which subjects will be randomly assigned, in a 1 to 1 ratio, to receive either galantamine or placebo once a day in the morning. Study drug will first be dispensed at the baseline visit. The treatment phase is composed of a titration period (the study drug will be introduced gradually) and a maintenance period and includes 9 visits (3 of which are conducted by telephone). The titration period is 12 weeks long, and visits occur about every 28 days. In the first 4 weeks of the titration period, subjects will receive either 8 mg galantamine or matching placebo, and this dose will be increased to 16 mg galantamine or placebo in the second 4 weeks. The dose will then be increased to 24 mg galantamine or placebo for the final 4 weeks of the titration period if the investigator believes the subject will benefit from and will safely tolerate 24 mg/day. If not, the subject may continue to receive 16 mg galantamine or placebo through the end of the titration period. After the titration period, subjects will enter the maintenance period and continue to take study drug at the dosage they received at the end of the titration period. This dosage may be continued through the end of the study or may be changed once (either up from 16 to 24 mg or down from 24 to 16 mg), depending upon the benefit and the safety of such a change for the individual patient as judged by the investigator. No dosage will exceed 24 mg/day. The posttreatment phase includes an End-of-Study Visit that occurs at the end of the maintenance period. A follow-up telephone contact (interview) is conducted 1 month after the End-of-Study Visit. The effectiveness of galantamine will be evaluated using the following tools: the Mini-Mental State Examination (MMSE); the Disability Assessment in Dementia (DAD); and the Assessment of Patient Accommodation Status and Caregiver Burden (APAS CarB). Safety evaluations for the study include the monitoring of vital status and institutionalization status, adverse events, vital signs, weight, physical and neurologic examinations. A Data Safety Monitoring Board, external to the company, has been commissioned for this study to monitor the progress of the study and to ensure that the safety of patients is not compromised. The effectiveness hypothesis of this study is that galantamine, 16 to 24 mg per day, is superior to placebo in reducing cognitive decline from baseline (start of study drug) as measured by the MMSE over the course of 2 years. The safety hypothesis is that the mortality rate in the galantamine 16 to 24 mg per day treatment group will be the same as that in the placebo group over the course of 2 years.

Official Title
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A Randomized, Double-Blind, Placebo-controlled Trial of Long-term (2-year) Treatment of Galantamine in Mild to Moderately-Severe Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Galantamine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Outpatients diagnosed with mild to moderately-severe, probable or possible AD, established in accordance with the criteria defined by the National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease Related Disorders Association or the Diagnostic and Statistical Manual, Fourth Edition living with or have regular and frequent visits from a responsible caregiver. Exclusion Criteria: Neurodegenerative disorders other than AD, such as Parkinson's Disease, Frontotemporal Dementia or Huntington's disease Any of specified conditions which may contribute to dementia any of specified coexisting diseases, including significant cardiovascular disease.

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Galantamine<br>Galantamine 8mg/ day oral capsule increased to 16mg/day then to 24 mg per day | Drug: Galantamine<br>* 8mg/ day oral capsule increased to 16mg/day then to 24 mg per day<br>|
| Placebo Comparator: Placebo<br>Matching placeco | Drug: Placebo<br>* Matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Mini-Mental State Examination (MMSE) Score | The MMSE is a brief 30-point questionnaire test that is used or the assessment of dementia patients' cognitive impairment. Evaluation of points are as follows: 24 to 30 = no cognitive impairment, 18 to 23 = mild cognitive impairment, 0 to 17 = severe cognitive impairment. Lower scores indicate worsening. | Baseline, Month 24 | 
| The Number of Deaths Reported in Participants | An external Data Safety Monitoring Board (DSMB) was assigned for this study to monitor the progress of the study and to ensure that the safety of participants was not compromised. | Up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Mini-Mental State Examination (MMSE) Score | The MMSE is a brief 30-point questionnaire test that is used or the assessment of dementia patients' cognitive impairment. Evaluation of points are as follows: 24 to 30 = no cognitive impairment, 18 to 23 = mild cognitive impairment, 0 to 17 = severe cognitive impairment. Lower scores indicate worsening. | Baseline, Month 6 | 
| Change From Baseline in Disability Assessment in Dementia (DAD) Scores | The DAD assesses physical activities of daily living and instrumental-activities of daily livings of participants with Alzheimer disease. This measure is a validated, disability assessment scale that collects information regarding the ability of a participant to initiate, plan, organize, and perform activities of daily living, as based on a structured interview with the caregiver. The maximum scores were 13 for initiation, 10 for planning and organizing, and 17 for effective performance in order to yield a total maximum score of 40. These scores were normalized to a scale of 100 for analysis.A higher score, or percentage of items that can be performed represents fewer disabilities in carrying out activities of daily living while a lower percentage indicates an increase in disabilities. | Baseline, Month 24 | 
| Change From Baseline in Patient Accommodation Measured Using the Assessment of Subject Accommodation Status and Caregiver Burden (APAS-CarB) | The APAS-CarB is a measure used to evaluate participant status and caregiver burden. The table below presents Patient Accommodation assessed as the percentage of participants home with friend or relative using the APAS-CarB. | Baseline, Months 12 and 24 | 
| Change From Baseline in Caregiver Time Spent With the Patient Measured Using the Assessment of Subject Accommodation Status and Caregiver Burden (APAS-CarB) | The table below presents the number of days that caregiving activities were provided during the past week. | Baseline, Months 12 and 24 | 
| Change From Baseline in Institutional Status | This table describes the number of participants who were reported as institutionalized at baseline and Month 24. | Baseline, Month 24 | 
| Change From Baseline in the Mini-Mental State Examination (MMSE) Subscales (Orientation, Registration, Attention and Calculation, Recall, and Language) | The MMSE, is a validated, brief examination that rates subjects on orientation (total score, 10), registration (total score, 3), attention (total score, 5), calculation (total score, 5), recall (total score, 3), and language (total score, 9). The maximum score is 30 (only the higher of the two scores for attention and calculation [each with a maximum score of 5] was used). A higher score compared with baseline indicates less impairment. | Baseline, Month 24 | 
| Change From Baseline in the Disability Assessment in Dementia (DAD) Subscales (Initiation, Planning and Organization, Effective Performance, Basic, Instrumental, and Leisure) | The DAD assesses physical activities of daily living and instrumental-activities of daily livings of participants with Alzheimer disease. This measure is a validated, disability assessment scale that collects information regarding the ability of a participant to initiate, plan, organize, and perform activities of daily living, as based on a structured interview with the caregiver. The maximum scores were 13 for initiation, 10 for planning and organizing, and 17 for effective performance in order to yield a total maximum score of 40. These scores were normalized to a scale of 100 for analysis.A higher score, or percentage of items that can be performed represents fewer disabilities in carrying out activities of daily living while a lower percentage indicates an increase in disabilities. | Baseline, Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's Disease, Galantamine, Dementia, Alzheimer type, Memory loss