Safety and Efficacy Study of Ladostigil in Mild to Moderate Probable Alzheimer's Disease

Study Overview
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Brief Summary
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For many, Alzheimer's disease is the number one medical issue facing our aging society. It is a late onset neurodegenerative disease, frequently under diagnosed, that impairs memory and cognitive performance. There are no known treatments that can either prevent or reverse its progression. Consequently, there still remains a need to evaluate treatments which can better stabilize the symptoms of this disease. These symptoms frequently include decreased functional capacity and negative psychological attributes (e,g, depression, anxiety) in association with the memory and cognition deficits. This current study is being done to assess an investigational compound that has been designed to not only improved the cognitive status of affected patients but to also better manage all symptoms. Hence, the ultimate goal is to provide patients with an improved quality of life by slowing the progression of this neurodegenerative disease

Detailed Description
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This is a phase II, proof of concept study to evaluate the safety and efficacy of the investigational compound ladostigil versus placebo in mild to moderate Alzheimer's disease patients. The randomized, double-blind, placebo-controlled phase of the trial will be 26 weeks in duration and will involve two cohorts (i.e. one arm receiving ladostigil and one arm receiving placebo). After the initial 26 week period, all participating subjects will receive 26 weeks of treatment with ladostigil (i.e. the open label phase). A total of five territories will be participating in this trial. These include Austria, Croatia, Germany, Serbia and Spain.

Official Title
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A 6-Month Prospective, Multi-Center, Double-Blind, Placebo-Controlled, Randomized, Adaptive-Trial-Design Study to Evaluate the Safety and Efficacy of 80mg b.i.d Ladostigil in Patients With Mild to Moderate Probable Alzheimer's Disease

Conditions
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Alzheimer's Disease, Dementia, Memory Loss, Cognitive Impairment

Intervention / Treatment
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* Drug: ladostigil hemitartrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: AD diagnosis according to NINCDS-ADRDA criteria Mild to moderate AD according to MMSE 14-24 inclusive MRI or CT assessment within 6 months before baseline, corroborating the clinical diagnosis and excluding other potential causes of dementia especially cerebrovascular lesions Absence of major depressive disease according to CSDD of less than or equal to 18 Modified Hachinski Ischemic Scale equal to or below 4 Education for eight or more years Previous decline in cognition for more than six months as documented in patient medical records A caregiver available and living in the same household or interacting with the patient daily and available if necessary to assure administration of investigational product Patients living at home or nursing home setting without continuous nursing care General health status acceptable for participation in a 12-month clinical trial and ability to swallow oral medication No history of treatment with rivastigmine For patients with either donepezil or galantamine anti-cholinesterase inhibitor treatment prescribed, stopped treatment four weeks prior to screening For patients with memantine treatment prescribed, stopped treatment four weeks prior to screening Exclusion Criteria: Other primary degenerative dementias (e.g. dementia with Lewy bodies, fronto-temporal dementia, Huntington's disease, Jacob-Creutzfeldt disease) Other neurodegenerative conditions (Parkinson's disease. amyotrophic lateral sclerosis, etc) Other central nervous system diseases (severe head trauma, tumors, subdural hematoma, etc) A current DSM-IV diagnosis of active major depression, schizophrenia or bipolar disorder Seizure disorders Other infectious, metabolic or systemic diseases affecting central nervous system (syphilis, present hypothyroidism, present vitamin B12 or folate deficiency, serum electrolytes out of normal range, juvenile onset diabetes mellitus, etc) Clinically significant, advanced or unstable disease that may interfere with primary or secondary variable evaluations Other unstable, chronic or clinically significant medical conditions involving major organs like kidney, liver, lungs and heart/vasculature Hospitalization or change of chronic concomitant medications one month prior to screening or during screening period

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 85 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: ladostigil hemitartrate<br>Ladostigil capsules 80 mg | Drug: ladostigil hemitartrate<br>* Final dosage strength of 80mg b.i.d will begin at Day 22 following a 21 day dose escalation phase involving 40mg and 60mg b.i.d dosage strengths. Oral, solid dosage.<br>|
| Placebo Comparator: Placebo<br>Placebo capsules | Drug: ladostigil hemitartrate<br>* Final dosage strength of 80mg b.i.d will begin at Day 22 following a 21 day dose escalation phase involving 40mg and 60mg b.i.d dosage strengths. Oral, solid dosage.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ADAS-Cog: Alzheimer's Disease Assessment Scale-Cognitive Subscale | Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) is a brief neuropsychological assessment used to assess the severity of cognitive symptoms of dementia, The ADAS-Cog consist of 11 questions: Word Recall Task Naming Objects and Fingers Following Commands Constructional Praxis Ideational Praxis Orientation Word Recognition Task Remembering Test Directions Spoken Language Comprehension Word-Finding Difficulty Item scores are summed. Low total scores indicate better cognitive performance. Minimum score 0 is best and maximum is 70 - worst. For the purposes of analyses the change from baseline is computed to each administration of the test. | 26 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neuropsychiatric Inventory (NPI) | The Neuropsychiatric Inventory (NPI) was developed to assess psychopathology in dementia patients. It evaluates 12 neuropsychiatric disturbances common in dementia: delusions, hallucinations, agitation, dysphoria, anxiety, apathy, irritability, euphoria, disinhibition, aberrant motor behavior, night-time behavior disturbances, and appetite and eating abnormalities. The severity and frequency of each neuropsychiatric symptom are rated on the basis of scripted questions administered to the patient's caregiver. Higher the score the more disturbed, lower score is thus better. Minimum score is 0 and maximum is 80. | 52 weeks | 
| Cornell Scale for Depression in Dementia (CSDD) | The Cornell Scale for Depression in Dementia (CSDD) was developed specifically to assess signs and symptoms of major depression in dementia on the basis of a semi-structured interview of a qualified informant. The CSDD evaluates a broad spectrum of depressive signs and synptoms and includes items from other depression scales. Information is obtained from interview of the caregiver as well as from direct observation and interview of the patient CSDD is a 19 item scale assessing depressive status. Higher score more depression. The scale ranges from 0-no depression to 38 maximum depression. | 52 weeks | 
| Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) | The Activities of Daily Living ADCS-ADL is a caregiver-based ADL scale composed of 23 items developed for use in dementia clinical trials. It is designed to assess the patient's performance of both basic and instrumental activities of daily living such as those necessary for personal care, communicating and interacting with other people, maintaining a household, conducting hobbies and interests as well as making judgments and decisions. For each ADL, the caregiver is asked whether the patient attempted the activity during the past four weeks. If the answer is positive, the caregiver is then asked to choose the single most accurate definition of the patient's level of performance. Assessment of functional activity status is a 23 item scale measuring impairment in functioning. The scale total score ranges from 0-profound impairment to 30 normal functioning (no impairments) | 52 weeks | 
| Mini-Mental State Examination | The MMSE is a frequently used screening instrument for AD drug studies. The instrument provides for evaluation of orientation, memory, attention, concentration, naming, repetition, comprehension, ability to create a sentence and to copy two intersecting polygons. This examination is frequently used by physicians in the original diagnosis of AD, and in its subsequent progression, because it can be easily performed in the routine care of patients. A lower score indicates more cognitive impairment. The highest (best) score is 30. The Mini-Mental State Examination, MMSE, is a 30-point questionnaire measures cognitive impairment to screen for dementia. Items are totaled. The scale ranges from 0-most impairment to 30 (normal) no impairment. | 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's Disease, Dementia, Memory Loss, Cognitive Impairment, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases, Neurodegenerative Diseases, Delirium, Dementia, Amnestic, Cognitive Disorders, Mental Disorders, Depression, Anxiety