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

NCT02035982 | Completed Phase 3

• 2 other identifiers: 107-2010Grant #12-74
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 2

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.

Conditions

Alzheimer's Disease; Dementia

Outcome Measures

Primary Outcomes (1)

• Clinician's Global Impression of Change (CGIC)

  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.

  baseline (0 weeks), 4 and 8 weeks

Secondary Outcomes (1)

• Number of total adverse events

  2, 4, and 8 weeks

Other Outcomes (10)

• Neuropsychiatric Inventory - nursing home version (NPI-NH)

  baseline (0 weeks), 4 and 8 weeks

• Severe Impairment Battery (SIB)

  baseline (0 weeks), 4 and 8 weeks

• The Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory, modified for severe AD (ADCS-ADL-sev)

  baseline (0 weeks), 4 and 8 weeks

Study Arms (2)

Cholinesterase Inhibitor

ACTIVE COMPARATOR

Participants randomized into the cholinesterase inhibitor arm will continue receiving their cholinesterase inhibitor at the same dosage.

Drug: Cholinesterase Inhibitor

Placebo

PLACEBO COMPARATOR

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

Interventions

Cholinesterase Inhibitor DRUG

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.

Also known as: Galantamine, Donepezil, Rivastigmine

Cholinesterase Inhibitor

Placebo DRUG

For participants randomized into the placebo intervention, placebo capsules will match capsules in the active intervention.

Placebo

Eligibility Criteria

• Age: 55 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Sunnybrook Health Sciences Centre: lead

Study Sites (2)

North York General Hospital

Toronto, Ontario, M2K1E1, Canada

Location

Sunnybrook Health Sciences Centre

Toronto, Ontario, M4N 3M5, Canada

Location

Related Publications (1)

• 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.

  PMID: 26482056 RESULT

MeSH Terms

Conditions

Alzheimer Disease; Dementia

Interventions

Cholinesterase Inhibitors; Galantamine; Donepezil; Rivastigmine

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Cholinergic Agents; Neurotransmitter Agents; Physiological Effects of Drugs; Amaryllidaceae Alkaloids; Alkaloids; Heterocyclic Compounds; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indans; Indenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Polycyclic Compounds; Phenylcarbamates; Carbamates; Acids, Acyclic; Carboxylic Acids

Study Officials

• Krista L. Lanctôt, PhD

  Sunnybrook Research Institute

  PRINCIPAL INVESTIGATOR

• Nathan Herrmann, MD

  Sunnybrook Health Sciences Centre

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 25, 2013
• First Posted: January 14, 2014
• Study Start: July 1, 2010
• Primary Completion: May 1, 2014
• Study Completion: September 1, 2015
• Last Updated: April 28, 2017

Record last verified: 2017-04

Locations

CA (2)