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Discontinuation of Cholinesterase Inhibitors for the Treatment of Severe Alzheimer's Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02035982
Recruitment Status : Completed
First Posted : January 14, 2014
Last Update Posted : April 28, 2017
Information provided by (Responsible Party):
Sunnybrook Health Sciences Centre

Brief Summary:

There are few pharmacological treatments available for Alzheimer's disease, including drugs called cholinesterase inhibitors: donepezil, galantamine, and rivastigmine. In research trials, cholinesterase inhibitors have been shown to improve memory and problem behaviours in people with mild to moderate Alzheimer's disease. However, these benefits may not extend to the real-world when taking into account nursing home and health care costs. There is less information on the use of cholinesterase inhibitors in people with severe Alzheimer's disease. In Canada, only donepezil is recommended for the treatment of severe Alzheimer's disease. However, there is no information on whether the benefits that donepezil provides to people with severe Alzheimer's disease are sustained over the long term. Moreover, while the tolerability of cholinesterase inhibitors is generally acceptable, their use is not completely harmless. Common side effects include nausea, diarrhea, insomnia, vomiting, muscle cramping, fatigue and loss of appetite.

In Ontario, cholinesterase inhibitor users tend to remain on these medications for two years or more and often until death. The current cholinesterase inhibitor guidelines provide details on what medication should be used, when it should be started and how it should be monitored, but there is less clarity on when it is safe and appropriate to stop treatment. The cessation of cholinesterase inhibitors in patients no longer appearing to display any clear benefits may help to lower the risk of unpleasant side effects, lower the use of multiple medications, and reduce the costs of caring for individuals with Alzheimer's disease. However, the cessation of cholinesterase inhibitor therapy may run the risk of deterioration in memory, worsening or development of behavioural symptoms and the placement of additional demands on professional and unpaid caregivers.

There is a clear need for guidelines when to stop cholinesterase inhibitor treatment, especially for patients in whom the benefits of not be on the medication will outweigh the risks. The purpose of this study is to address this issue by collecting data which may be helpful in predicting which types of patients may benefit from stopping cholinesterase inhibitor treatment. Understanding when, and for whom, it is appropriate to stop cholinesterase inhibitor treatment will influence the field of pharmacology in the treatment of Alzheimer's disease.

Condition or disease Intervention/treatment Phase
Alzheimer's Disease Dementia Drug: Cholinesterase Inhibitor Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Discontinuation of Cholinesterase Inhibitors for the Treatment of Severe Alzheimer's Disease in Long Term Care Setting
Study Start Date : July 2010
Actual Primary Completion Date : May 2014
Actual Study Completion Date : September 2015

Resource links provided by the National Library of Medicine

Drug Information available for: Galantamine

Arm Intervention/treatment
Active Comparator: Cholinesterase Inhibitor
Participants randomized into the cholinesterase inhibitor arm will continue receiving their cholinesterase inhibitor at the same dosage.
Drug: Cholinesterase Inhibitor

For participants randomized into the active treatment arm, they will be provided with the following study medications:

Donepezil - 5 mg or 10 mg Galantamine - 8 mg and 16 mg and 24 mg Rivastigmine - 1.5 mg and 3 mg

The type of study medication provided will depend on the type and dosage of the cholinesterase inhibitor they have been receiving for the last 3 months of their regular treatment. For example, if that have been taking Donepezil - 5 mg daily, they will continue on that same medication, dosage and frequency.

Other Name: Galantamine, Donepezil, Rivastigmine

Placebo Comparator: Placebo
Participants randomized into the placebo arm will be tapered off their cholinesterase inhibitor for the first 2 weeks. For the remaining 6 weeks of their study they will be receiving only placebo, and no cholinesterase inhibitor.
Drug: Placebo
For participants randomized into the placebo intervention, placebo capsules will match capsules in the active intervention.

Primary Outcome Measures :
  1. Clinician's Global Impression of Change (CGIC) [ Time Frame: baseline (0 weeks), 4 and 8 weeks ]
    CGIC score is used as a measure of clinically meaningful change, as distinct from an instrument's ability to assess any change. This scale is completed by the clinician.

Secondary Outcome Measures :
  1. Number of total adverse events [ Time Frame: 2, 4, and 8 weeks ]
    All emerging adverse events (AEs) will be noted and followed-up until resolution. The total number of adverse events within each intervention arm will be compared between groups.

Other Outcome Measures:
  1. Neuropsychiatric Inventory - nursing home version (NPI-NH) [ Time Frame: baseline (0 weeks), 4 and 8 weeks ]
    The NPI-NH will allow us to monitor and assess the change in the following neuropsychiatric symptoms: delusions, hallucinations, agitation, depression/dysphoria, anxiety, euphoria/elation, apathy/indifference, disinhibition, irritability/lability, aberrant motor behaviour, sleep, and appetite/eating disorders.

  2. Severe Impairment Battery (SIB) [ Time Frame: baseline (0 weeks), 4 and 8 weeks ]
    The SIB will allow us to assess cognition our participant group, who are too impaired to complete other standard neuropsychological tests. The SIB will allow us to detect changes in different domains of cognition (social interaction, memory, orientation, language, attention, praxis, visuospatial ability, constrution and orientation to name).

  3. The Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory, modified for severe AD (ADCS-ADL-sev) [ Time Frame: baseline (0 weeks), 4 and 8 weeks ]
    ADCS-ADL-sev assesses functional capacity based on 19 questions assessing various activities of daily living

  4. Mini-Mental State Examination (MMSE) [ Time Frame: screening (-1 weeks), baseline (0 weeks), 2, 4 and 8 weeks ]
    The MMSE will assess the severity of cognitive impairment and will provide a measurement of change in cognitive impairment between assessments.

  5. Apathy Evaluation Scale (AES) [ Time Frame: baseline (0 weeks), 4 and 8 weeks ]
    AES is an 18-item scale measuring apathy resulting from brain-related pathology.

  6. Cohen-Mansfield Agitation Inventory (CMAI) [ Time Frame: baseline (0 weeks), 4 and 8 weeks ]
    The CMAI is a 29-point scale that measures agitation in two dimensions; verbal and physical, each of which having two poles, aggressive and non-aggressive. The degree of agitation will be compared within and between intervention groups.

  7. Cornell Depression Scale for Dementia (Cornell) [ Time Frame: baseline (0 weeks), 4 and 8 weeks ]
    The CSDD is a scale assessing signs and symptoms of major depression in patients with dementia. This scale is completed by the caregiver, not the patient. The scale encompasses areas of mood-related signs, behavioural disturbance, physical signs, cyclic functions, and ideational disturbance.

  8. Quality of Life in Late Stage Dementia (QUALID) [ Time Frame: baseline (0 weeks) and 8 weeks ]
    The QUALID is an 11 item questionnaire completed by the caregiver. This questionnaire rates the quality of life in persons with late stage Alzheimer's disease and other dementing illnesses.

  9. Udvalg for Kliniske Undersøgelser (UKU) side effect rating scale [ Time Frame: baseline (0 weeks), 2, 4 and 8 weeks ]
    The UKU is a 53 item scale measuring side effects related to the study medication. This scale accounts for psychic, neurologic, autonomic and other symptoms.

  10. Number of p.r.n (as needed) medications used to treat behavioural and psychological symptoms of dementia (BPSD) [ Time Frame: baseline (0 weeks), 2, 4 and 8 weeks. ]
    The number of p.r.n medications administered to the patient is calculated every two weeks.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   55 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Aged >55 years
  • Meet Diagnostic and Statistical Manual - IV (DSM-IV) criteria for primary degenerative dementia
  • Meet National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria for probable AD of at least one year's duration
  • Score ≤15 on the Mini-Mental State Examination (MMSE) (severe dementia)
  • Receiving donepezil (5 or 10 mg), galantamine (8, 16 or 24 mg) or rivastigmine (3, 4.5 or 6 mg oral) for at least 2 years, with a stable dose for at least 3 months prior to study entry
  • Patients with a current order for any regularly administered psychotropic (e.g. selective serotonin reuptake inhibitor (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), trazodone, atypical or typical antipsychotics) must have been on a stable dose for at least 1 month prior to study entry

Exclusion Criteria:

  • Patients with the following conditions will be excluded:
  • Dementia due to any etiology other than Alzheimer's Disease (AD)
  • Significant difficulty ingesting oral medications
  • Current evidence of any uncontrolled medical illness that would interfere with the subject's participation in the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02035982

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Canada, Ontario
North York General Hospital
Toronto, Ontario, Canada, M2K1E1
Sunnybrook Health Sciences Centre
Toronto, Ontario, Canada, M4N 3M5
Sponsors and Collaborators
Sunnybrook Health Sciences Centre
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Principal Investigator: Krista L. Lanctôt, PhD Sunnybrook Research Institute
Principal Investigator: Nathan Herrmann, MD Sunnybrook Health Sciences Centre
Publications of Results:
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Responsible Party: Sunnybrook Health Sciences Centre Identifier: NCT02035982    
Other Study ID Numbers: 107-2010
Grant #12-74 ( Other Grant/Funding Number: Alzheimer Society of Canada Research Program )
First Posted: January 14, 2014    Key Record Dates
Last Update Posted: April 28, 2017
Last Verified: April 2017
Additional relevant MeSH terms:
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Alzheimer Disease
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Cholinesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Cholinergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Nootropic Agents
Autonomic Agents
Peripheral Nervous System Agents
Neuroprotective Agents
Protective Agents