Efficacy of Circadin® 2 mg in Patients With Mild to Moderate Alzheimer Disease Treated With AChE Inhibitor

Study Overview
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Brief Summary
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The aim of this exploratory randomized, placebo controlled study is to evaluate the efficacy of Circadin® 2mg in patients with mild to moderate Alzheimer Disease (AD) treated with the acetylcholinesterase (AChE) inhibitor. The effects of add-on Circadin® 2mg vs. placebo on the decline in cognitive skills and global functioning, as well as on daytime somnolence and will be assessed.

Official Title
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A Double-blind, Parallel Group, Randomized, Placebo Controlled Study of the Efficacy of Circadin® 2mg in Patients With Mild to Moderate Alzheimer Disease (AD) Treated With Acetylcholinesterase (AChE) Inhibitor

Conditions
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Alzheimer's Disease, Sleep Disorder

Intervention / Treatment
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* Drug: Circadin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent as dictated by local legal circumstances. Age range: adult patients between 50-85 years of age. Gender: men and women. Women of child bearing potential or within two years of the menopause must have a negative urine pregnancy test at the Screening Visit. A documented history of confirmed Alzheimer's disease Dementia severity: MMSE score > 15, Stable AChE inhibitor dose for 2 months prior to Screening visit. Stable medications for non-excluded concurrent medical conditions for four weeks prior to the screening visit. Stable doses of B12 and/or Folic acid supplements for at least 3 months prior to enrollment and throughout the study. Cranial image: no evidence of focal disease to account for dementia (established by CT, PET or MRI). If there is no such available scan (CT, PET or MRI), one must be performed prior to enrollment. Health: Physically acceptable for the study with no pathology likely to occur during or immediately after the study, as confirmed by medical history and exam and ECG. Clinical laboratory values must be within normal limits, or judged not clinically significant by the investigator. Residence: Stable home situation with no planned move during the 28-week investigational period. A family member or a regular caregiver that will be available for visits and will ensure compliance. The caregiver must speak fluent Hebrew, Russian or English. Ability to ingest oral medication and participate in all scheduled evaluations. Ability to spend 2 daily hours outdoors exposed to sunlight. Exclusion Criteria: Severe agitation. Unstable medical condition, mental retardation. moderate to severe depression as defined by DSM-IV Use of benzodiazepines or other hypnotics during the study and the preceding four weeks. Use of Circadin® during the two weeks prior to study enrollment. Pharmacological immunosuppression. Participation in a clinical trial with any investigational agent within two months prior to study enrollment. Alcoholism. Known or suspected hypersensitivity to exogenous melatonin or melatonin receptor agonists. Patients with rare hereditary problems of galactose intolerance, the LAPP lactose deficiency or glucose mal absorption. Renal Failure with creatinine >150 micromol/l. Hepatic Failure with ASAT; ALAT; GGT levels above three times the upper normal limit. Clinically significant abnormal laboratory findings which have not been approved by the Safety Officer (sponsor) Other serious diseases that could interfere with patient assessment. Caregivers who are unwilling or unable to give informed consent or otherwise fulfill requirements of the study. Untreated B12 and/or Folic acid deficiency.

Ages Eligible for Study
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Minimum Age: 50 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: Circadin<br>Drug | Drug: Circadin<br>* Prolonged Release melatonin (Circadin) 2mg tablets<br>|
| Placebo Comparator: Placebo<br>drug | Drug: Placebo<br>* Matched placebo tablets, with identical features to the Circadin tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 24 Weeks in ADAS-cog | ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale) is a cognitive testing instrument used in clinical trials. It consists of 11 tasks measuring the disturbances of memory, language, praxis, attention, and other cognitive abilities that are often referred to as the core symptoms of AD. The test comprises 11 items summed to a total score ranging from 0 to 70, with lower scores indicating less severe impairment. A negative change indicates an improvement from baseline. ADAS-cog was measured at base line and at end of treatment after 24 weeks. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to 24 Weeks in iADL | Instrumental Activities of Daily Living (iADL). The scale rates activities that represent key life tasks that people need to manage. These tasks are valuable for evaluating persons with early-stage disease, both to assess the level of disease and to determine the person's ability to care for himself or herself. Scores of 0 or 1 are given to every task (Bathing, Dressing, Tolieting, transferring, Continence and Feeding) to a total score of 6. , while 0 represents a patient who is very dependent and 6 represents patient who is independent. iADL was measured at base line and at end of treatment after 24 weeks. | 24 weeks | 
| Change From Baseline to 24 Weeks in MMSE | The Mini Mental State Examination (MMSE) is a brief assessment instrument used to assess cognitive function in elderly patients. The MMSE can be used to screen for cognitive impairment and as a measurement of cognition over time and with pharmacologic treatment. The instrument is divided into 2 sections. The first section measures orientation, memory, and attention: the maximum score is 21. The second section tests the ability of the patient to name objects, follow verbal and written commands, write a sentence, and copy figures: the maximum score is 9. The scoring range for the MMSE is 0-30. Higher score represents better performance. MMSE was measured at base line and at end of treatment after 24 weeks. | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's Disease, Acetylcholinesterase inhibitor, cognitive function, Circadin, Sleep disturbances