Clinical trial NCT02035982: Discontinuation of Cholinesterase Inhibitors for the Treatment of Severe Alzheimer's Disease
Official title: A Discontinuation of Cholinesterase Inhibitors for the Treatment of Severe Alzheimer's Disease in Long Term Care Setting
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Alzheimer's Disease
Dementia
Lead sponsor: Sunnybrook Health Sciences Centre
Sponsor class: OTHER
First posted: 2014-01-14
Enrollment: 40
Sex: ALL
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: 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

Primary outcomes:
measure: Clinician's Global Impression of Change (CGIC)
timeFrame: baseline (0 weeks), 4 and 8 weeks
Secondary outcomes:
measure: Number of total adverse events
timeFrame: 2, 4, and 8 weeks
Other outcomes:
measure: Neuropsychiatric Inventory - nursing home version (NPI-NH)
timeFrame: baseline (0 weeks), 4 and 8 weeks
measure: Severe Impairment Battery (SIB)
timeFrame: baseline (0 weeks), 4 and 8 weeks
measure: The Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory, modified for severe AD (ADCS-ADL-sev)
timeFrame: baseline (0 weeks), 4 and 8 weeks
measure: Mini-Mental State Examination (MMSE)
timeFrame: screening (-1 weeks), baseline (0 weeks), 2, 4 and 8 weeks
measure: Apathy Evaluation Scale (AES)
timeFrame: baseline (0 weeks), 4 and 8 weeks
measure: Cohen-Mansfield Agitation Inventory (CMAI)
timeFrame: baseline (0 weeks), 4 and 8 weeks
measure: Cornell Depression Scale for Dementia (Cornell)
timeFrame: baseline (0 weeks), 4 and 8 weeks
measure: Quality of Life in Late Stage Dementia (QUALID)
timeFrame: baseline (0 weeks) and 8 weeks
measure: Udvalg for Kliniske Undersøgelser (UKU) side effect rating scale
timeFrame: baseline (0 weeks), 2, 4 and 8 weeks
measure: Number of p.r.n (as needed) medications used to treat behavioural and psychological symptoms of dementia (BPSD)
timeFrame: baseline (0 weeks), 2, 4 and 8 weeks.
Locations:
city: Toronto
country: Canada
facility: North York General Hospital
state: Ontario
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
Study officials:
affiliation: Sunnybrook Research Institute
name: Krista L. Lanctôt, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Sunnybrook Health Sciences Centre
name: Nathan Herrmann, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Herrmann N, O'Regan J, Ruthirakuhan M, Kiss A, Eryavec G, Williams E, Lanctot KL. A Randomized Placebo-Controlled Discontinuation Study of Cholinesterase Inhibitors in Institutionalized Patients With Moderate to Severe Alzheimer Disease. J Am Med Dir Assoc. 2016 Feb;17(2):142-7. doi: 10.1016/j.jamda.2015.08.019. Epub 2015 Oct 9.