Clinical Trial Summary
Dementia is a chronic progressive mental disorder that adversely affects higher cortical
functions, including cognition and behavior leading up to disability and dependence in daily
life activities. It has become a major public health concern because of its increasing
prevalence, chronicity, burden for caregivers, and the high personal and financial costs
needed for care. Alzheimer disease (AD) is the most prevalent form of dementia, occurring in
5% to 7% of individuals older than 60. In Portugal, Santana et al study estimated that 160
287 people above 60 years had a diagnosis of dementia in 2013 (prevalence of 5,9%).The
increasing national and international prevalence of dementia and its associated burden then
imparts a high priority on delivering safe and effective treatment options.
Currently approved treatments available for the symptomatic management of mild to moderate AD
include cholinesterase inhibitors (ChEIs) (donepezil, rivastigmine, and galantamine) and a
N-methyl- D-aspartate receptor antagonist (memantine). These drugs are also given off-label
for other types of dementia (vascular and mixed dementias), with treatment continuing through
advanced disease stages. Given that ChEIs have demonstrated short-term modest stabilization
on measures of cognition and global functioning in randomized controlled trials (RCTs),
several practice guidelines have proposed ChEIs for the treatment of all stages of AD, with
some advocating ChEI discontinuation if tolerability issues arise, or if there is no longer a
noticeable clinical benefit. Further studies in this setting are important as patients with
severe dementia are more functionally impaired, present with comorbid illnesses, posing a
higher risk of polypharmacy. In addition, ChEIs have a potential risk of adverse events
including nausea, diarrhea, insomnia, vomiting, muscle cramping, fatigue, and weight loss.
Less commonly, ChEI might be associated with rhabdomyolysis, convulsions, falls, syncope,
pneumonia and death. Because cognitive and behavioral impairments change during the
progressive disease course, the effects of medications may be unpredictable, especially over
long durations of treatment. It might be challenging to weigh minimally beneficial effects
against predicted harms of continued treatment, considering both patient and
caregiver-centered care goals besides less clinically relevant cognitive outcomes.
Only a small number of discontinuation RCTs were conducted to date but involved relatively
few participants with heterogeneous designs, disease severities and outcomes. As so,
clinicians take individualized discontinuation decisions and the only consensual domains are
a lack of response and a loss of effectiveness. The present pragmatic clinical trial will
compare the efficacy of maintaining pharmacological treatment versus treatment cessation on
cognition, behavior, functional disability and quality of life of patients and caregivers,
among patients with severe dementia due to AD, with or without small vessel subcortical
vascular disease. The investigators will consider other important endpoints besides cognitive
functioning including mood, apathy, energy and neuropsychiatric symptoms. Moreover, this
trial will try to look for outcomes that engage patients and families in treatment decisions.
Specific aim 1. Explore the effects of discontinuing ChEI and/or memantine on global
impression, disease severity, function, behavior and cognitive outcomes;
Hypothesis:
1. Progression to disability (defined as a loss of 2 of 4 basic functions, or 6 of 11
instrumental functions, according to the BADLS), at 6 months, is significantly higher in
patients discontinuing therapy;
2. Patients with severe dementia who discontinue ChEI and/or memantine show a significantly
higher decline on ratings of cognitive function, behavior and activities of daily living
over 6 months than those continuing these drugs;
3. Patients with severe dementia who discontinue ChEI and/or memantine experience increased
adverse events including healthcare visits and other several medical intercurrences.
Specific aim 2. Explore the effects of discontinuation strategies in patients and caregiver's
health related quality of life.
Hypothesis:
a) Patients with severe dementia and their caregivers experience lower levels of
health-related quality of life after treatment discontinuation.
Specific aim 3. Cost-utility and cost-effectiveness analysis of a discontinuation strategy.
a) Treatment with antidementia drugs is the most cost-effective treatment strategy in
advanced stages of dementia, delaying progression to disability and reducing formal and
informal costs and healthcare utilization;
a) Treatment with antidementia drugs is the strategy associated with better quality of life
and lower cost-utility ratio.
