Donepezil and Memantine in Moderate to Severe Alzheimer's Disease - Full Text View

Sponsored by:	King's College London
Information provided by:	King's College London
ClinicalTrials.gov Identifier:	NCT00866060

Purpose

The trial will examine whether pharmacological treatment with donepezil, memantine or combination of memantine and donepezil is any better than a placebo (dummy) treatment in people with Alzheimer's disease who have reached the moderate to severe stage of illness. Using a double blind design, where neither the investigators nor participants know who is receiving which treatment, participants will be randomly assigned to one of these four treatment groups (donepezil and memantine, memantine only, donepezil only or placebo). In order to keep both the investigators and participants blind to drug allocation a double dummy design will be necessary. This means that each participant will receive 2 treatments − either an active form or placebo of each of the 2 study drugs.

Hypotheses are:

Patients with Alzheimer's disease (AD) who continue donepezil beyond the point of transition from moderate to severe dementia continue to show significantly less decline on ratings of cognitive function and activities of daily living over the following 12 months than those discontinuing donepezil.
Patients with AD who change to memantine therapy in place of donepezil at the point of transition from moderate to severe dementia show significantly smaller decline on ratings of cognitive function and activities of daily living over the following 12 months than those who receive placebo.
Patients given the combination of memantine and donepezil at the point of transition from moderate to severe dementia show significant additive or synergistic benefits on measures of activities of daily living and cognitive function after 12 months compared to those patients continuing on either drug as a single treatment.

Condition	Intervention	Phase
Moderate to Severe Alzheimer's Disease	Drug: Memantine Drug: Donepezil Drug: Placebo donepezil Drug: Placebo memantine	Phase IV

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Factorial Assignment, Efficacy Study
Official Title:	Donepezil and Memantine in Moderate to Severe Alzheimer's Disease

Resource links provided by NLM:

Genetics Home Reference related topics: Alzheimer disease

MedlinePlus related topics: Alzheimer's Disease Dementia

Drug Information available for: Memantine Memantine hydrochloride E 2020 Donepezil

U.S. FDA Resources

Further study details as provided by King's College London:

Primary Outcome Measures:

Cognitive Function measured with the Standardised MMSE (SMMSE). [ Time Frame: 4 years ] [ Designated as safety issue: No ]
Activities of Daily Living measured with the Bristol Activities of Daily Living scale (BADLS). [ Time Frame: 4 years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Non−cognitive dementia symptoms measured with the Neuropsychiatric Inventory (NPI) and the Cohen−Mansfield Agitation Inventory. [ Time Frame: 4 years ] [ Designated as safety issue: No ]
Health−related quality of life measured with the EQ−5D (Euroqol Group 1990) and the DEMQOL−Proxy (Smith et al 2004) − a carer−rated and disease−specific measure of quality of life in dementia. [ Time Frame: 4 years ] [ Designated as safety issue: No ]
Care−giver burden measured with the General Health Questionnaire. [ Time Frame: 4 years ] [ Designated as safety issue: No ]
Cost effectiveness assessed through consideration of the combination of costs generated from the Client Service Receipt Inventory (CSRI) and the assessments of function and quality of life (BADLS, DEMQOL, EQ−5D). [ Time Frame: 4 years ] [ Designated as safety issue: No ]
Institutionalisation defined as permanent transition from living in an independent household to a care home, NHS continuing care unit or hospital and measured with questions taken from the CSRI and telephone interviews. [ Time Frame: 4 years ] [ Designated as safety issue: No ]

Estimated Enrollment:	800
Study Start Date:	February 2008
Estimated Study Completion Date:	June 2013
Estimated Primary Completion Date:	February 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Active Comparator 10mg donepezil plus 20mg memantine Participants in this arm will continue with their current donepezil 10mg/day regimen and immediately commence active memantine at a dose of 5mg per day, increasing in 5mg increments weekly until 20mg per day is achieved from week 4 onwards	Drug: Memantine 20mg memantine Drug: Donepezil 10mg donepezil
2: Placebo Comparator Placebo donepezil plus 20mg memantine Participants in this arm will immediately commence active memantine at a dose of 5mg per day, increasing in 5mg increments weekly until 20mg per day is achieved from week 4 onwards. Donepezil dose will be reduced to 5mg daily in weeks 1 to 4 and replaced with placebo donepezil in week 5.	Drug: Memantine 20mg memantine Drug: Placebo donepezil Placebo donepezil
3: Placebo Comparator 10mg donepezil plus placebo memantine Participants in this arm will continue with their current donepezil 10mg/day regimen and immediately commence placebo memantine.	Drug: Donepezil 10mg donepezil Drug: Placebo memantine Placebo memantine
4: Placebo Comparator Placebo donepezil plus placebo memantine Participants in this arm will immediately commence placebo memantine dose escalation and will switch to donepezil 5mg daily in weeks 1 to 4, and replaced with placebo donepezil in week 5.	Drug: Placebo donepezil Placebo donepezil Drug: Placebo memantine Placebo memantine

Detailed Description:

This trial will involve the withdrawal of drug participants that are currently on (donepezil) and in arm 4, the participant will only be on placebo treatment. It is important to include this arm of the study as a key objective in looking at the benefit of continuing donepezil and therefore a placebo arm should be present as a comparator. To reduce the risk to participants of withdrawing donepezil too early in their illness, an inclusion criteria is that the participant is at a stage in their disease whereby the prescribing clinician feels a change in drug prescription may be appropriate.

Eligibility

Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Participants will be patients who meet NINCDS-ADRDA criteria for probable or possible Alzheimer's disease (McKhann et al, 1984). In addition they will meet all of the following criteria:

SMMSE = 5 to 13 (13 chosen as NICE threshold of 10 plus 1 SD on SMMSE score)
Continuously prescribed donepezil for at least 3 months
Maintained on 10mg donepezil in previous 6 weeks.
No changes in prescription of any psychotropic (antipsychotic, antidepressant, benzodiazepine) medication in previous 6 weeks.
Prescribing clinician considers (based on NICE guidance, discussions with patient and carer and clinical judgement) that change of drug treatment (i.e. stop donepezil or introduce memantine) may be appropriate.
Patient is community resident and has family or professional carer or is visited on at least a daily basis by carer.
Patient agrees to participate if considered capable (see section 7.5)
Main carer (informal or professional) consents to their own involvement and the patient's involvement -

Exclusion Criteria:

To maximise the generalisability of the study data, exclusions will be kept to a minimum. These will include:

Patient has severe, unstable or poorly controlled medical conditions apparent from physical examination or clinical history.
Patient is already prescribed memantine.
Patient is unable to take trial medications because of contra-indications or previous adverse or allergic reactions.
Patient is involved in another clinical trial.
Clinician considers patient would not be compliant with trial medication. -

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00866060

Locations

United Kingdom
Institute of Psychiatry	Recruiting
London, United Kingdom, SE5 8AF
Contact: Robert J Howard, MD 020 7848 0545 r.howard@iop.kcl.ac.uk
Principal Investigator: Robert J Howard, MD

Sponsors and Collaborators

King's College London

Investigators

Principal Investigator:

Robert J Howard, MD

Institute of Psychiatry

More Information

Additional Information:

DOMINO-AD Trial This link exits the ClinicalTrials.gov site

No publications provided

Responsible Party:	King's College London ( Dr Gill Dale )
Study ID Numbers:	2006/123, ISRCTN49545035, Eudract 2007-001172-36
Study First Received:	March 19, 2009
Last Updated:	March 19, 2009
ClinicalTrials.gov Identifier:	NCT00866060 History of Changes
Health Authority:	United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by King's College London:

donepezil
memantine
moderately severe Alzheimer's disease
severe Alzheimer's disease

Study placed in the following topic categories:

Nootropic Agents
Excitatory Amino Acids
Neurotransmitter Agents
Alzheimer Disease
Central Nervous System Diseases
Cholinergic Agents
Brain Diseases
Neurodegenerative Diseases
Cognition Disorders

Cholinesterase Inhibitors
Delirium, Dementia, Amnestic, Cognitive Disorders
Dopamine
Mental Disorders
Donepezil
Memantine
Dopamine Agents
Dementia
Delirium

Additional relevant MeSH terms:

Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anti-Dyskinesia Agents
Physiological Effects of Drugs
Antiparkinson Agents
Excitatory Amino Acid Agents
Neurodegenerative Diseases
Brain Diseases
Cholinergic Agents
Mental Disorders
Therapeutic Uses
Donepezil
Memantine

Dementia
Excitatory Amino Acid Antagonists
Nootropic Agents
Nervous System Diseases
Alzheimer Disease
Central Nervous System Diseases
Enzyme Inhibitors
Pharmacologic Actions
Cholinesterase Inhibitors
Delirium, Dementia, Amnestic, Cognitive Disorders
Dopamine Agents
Tauopathies
Central Nervous System Agents

ClinicalTrials.gov processed this record on August 25, 2009