Withdrawal of Antidementia Drugs in Advanced Dementia (WADAD)

NCT05321680 | Completed DMC

• 1 other identifier: 68-21
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Dementia

Keywords

antidementia drug; dementia; quality of life; cost-utility analysis

Outcome Measures

Primary Outcomes (2)

• BADLS (Bristol Activities of Daily Living Scale)

  Progression to disability (defined as a loss of 2 of 4 basic functions, or 6 of 11 instrumental functions); total score varies from 0 (totally independent) to 60 (totally dependent)

  6 months

• Quality of life of patients and caregivers

  EuroQol-5D (EQ-5D); score varies from 0 to 100 using a Visual analogue scale

  6 months

Secondary Outcomes (5)

• Neuropsychiatric inventory (NPI)

  6 months

• General Health Questionnaire 12 (caregivers)

  6 months

• Clinical Global Impression of Change plus Caregiver Input (CGIC-Plus)

  6 months

• Serious adverse events

  6 months

• Mortality

  6 months

Study Arms (2)

Treatment withdrawal

EXPERIMENTAL

discontinuation of treatment (anti-cholinesterase inhibitors including donepezil, rivastigmine and galantamine; and/or memantine)

Other: Treatment withdrawal

Treatment continuation

NO INTERVENTION

treatment continuation (anti-cholinesterase inhibitors including donepezil, rivastigmine and galantamine; and/or memantine)

Interventions

Treatment withdrawal OTHER

Tapering or suspension of antidementia drugs

Treatment withdrawal

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of dementia syndrome defined by clinical criteria (Alzheimer's dementia according to NIA-AA 2011 criteria, vascular dementia or mixed dementia)
• MMSE≤15
• Medicated with oral/transdermal patch anti-dementia (donepezil, rivastigmine, galantamine or memantine), alone or in combination, for a minimum period of 3 months;
• Availability of a designated caregiver who monitors the patient's clinical situation and can collaborate in the assessment of outcomes and the provision of informed consent (ideally 8/h at least 3x/week)
• Shared perception between the attending neurologist and family members that the drug may no longer have a therapeutic effect, has been ineffective after a therapeutic trial, or the presence of side effects possibly attributed to the drugs.

You may not qualify if:

• Life expectancy presumably less than the follow-up period (6 months);
• Unstable medical or surgical condition that can significantly interfere with the patient's overall health status;
• Another pathology interfering with cognitive functioning (HIV, brain tumor, encephalitis, demyelinating disease);
• Introduction of an antipsychotic drug in the last month.

Sponsors & Collaborators

• Centro Hospitalar De São João, E.P.E.: lead

Study Sites (1)

Centro Hospitalar Universitário de São João

Porto, 4200-319, Portugal

Location

MeSH Terms

Conditions

Dementia

Condition Hierarchy (Ancestors)

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

Study Officials

• Verónica R Cabreira, MD

  Centro Hospitalar São João (Neurology Department)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: anonimized data
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: A clinical, pragmatic, unicentric, open trial with blinded assessors. We will use a parallel randomized design (1:1) that will evaluate the effect of maintaining pharmacological treatment versus treatment withdrawal.

Study Record Dates

• First Submitted: March 23, 2022
• First Posted: April 11, 2022
• Study Start: March 1, 2021
• Primary Completion: December 1, 2021
• Study Completion: March 20, 2022
• Last Updated: April 11, 2022

Record last verified: 2022-04

Locations

PT (1)