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Donepezil and Memantine in Moderate to Severe Alzheimer's Disease (DOMINO-AD)

Primary Purpose

Moderate to Severe Alzheimer's Disease

Status

Unknown status

Phase

Phase 4

Locations

United Kingdom

Study Type

Interventional

Intervention

Memantine

Donepezil

Placebo donepezil

Placebo memantine

About this trial

This is an interventional treatment trial for Moderate to Severe Alzheimer's Disease focused on measuring donepezil, memantine, moderately severe Alzheimer's disease, severe Alzheimer's disease

Eligibility Criteria

undefined - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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. -

Sites / Locations

Institute of PsychiatryRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Arm Description

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

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.

10mg donepezil plus placebo memantine Participants in this arm will continue with their current donepezil 10mg/day regimen and immediately commence placebo memantine.

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.

Outcomes

Primary Outcome Measures

Cognitive Function measured with the Standardised MMSE (SMMSE).

Activities of Daily Living measured with the Bristol Activities of Daily Living scale (BADLS).

Secondary Outcome Measures

Non-cognitive dementia symptoms measured with the Neuropsychiatric Inventory (NPI) and the Cohen-Mansfield Agitation Inventory.

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.

Care-giver burden measured with the General Health Questionnaire.

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).

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.

Full Information

NCT ID

NCT00866060

First Posted

March 19, 2009

Last Updated

March 19, 2009

Sponsor

King's College London

1. Study Identification

Unique Protocol Identification Number

NCT00866060

Brief Title

Donepezil and Memantine in Moderate to Severe Alzheimer's Disease

Acronym

DOMINO-AD

Official Title

Donepezil and Memantine in Moderate to Severe Alzheimer's Disease

Study Type

Interventional

2. Study Status

Record Verification Date

March 2009

Overall Recruitment Status

Unknown status

Study Start Date

February 2008 (undefined)

Primary Completion Date

February 2012 (Anticipated)

Study Completion Date

June 2013 (Anticipated)

3. Sponsor/Collaborators

Name of the Sponsor

King's College London

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Moderate to Severe Alzheimer's Disease

Keywords

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Factorial Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Allocation

Randomized

Enrollment

800 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Arm Type

Active Comparator

Arm Description

Arm Title

Arm Type

Placebo Comparator

Arm Description

Arm Title

Arm Type

Placebo Comparator

Arm Description

10mg donepezil plus placebo memantine Participants in this arm will continue with their current donepezil 10mg/day regimen and immediately commence placebo memantine.

Arm Title

Arm Type

Placebo Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

Memantine

Other Intervention Name(s)

Ebixa

Intervention Description

20mg memantine

Intervention Type

Drug

Intervention Name(s)

Donepezil

Other Intervention Name(s)

Aricept

Intervention Description

10mg donepezil

Intervention Type

Drug

Intervention Name(s)

Placebo donepezil

Intervention Description

Placebo donepezil

Intervention Type

Drug

Intervention Name(s)

Placebo memantine

Intervention Description

Placebo memantine

Primary Outcome Measure Information:

Title

Cognitive Function measured with the Standardised MMSE (SMMSE).

Time Frame

4 years

Title

Activities of Daily Living measured with the Bristol Activities of Daily Living scale (BADLS).

Time Frame

4 years

Secondary Outcome Measure Information:

Title

Non-cognitive dementia symptoms measured with the Neuropsychiatric Inventory (NPI) and the Cohen-Mansfield Agitation Inventory.

Time Frame

4 years

Title

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

Title

Care-giver burden measured with the General Health Questionnaire.

Time Frame

4 years

Title

Time Frame

4 years

Title

Time Frame

4 years

10. Eligibility

Sex

All

Accepts Healthy Volunteers

Eligibility 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. -

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Robert J Howard, MD

Organizational Affiliation

Institute of Psychiatry

Official's Role

Principal Investigator

Facility Information:

Facility Name

Institute of Psychiatry

City

London

ZIP/Postal Code

SE5 8AF

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Robert J Howard, MD

Phone

020 7848 0545

r.howard@iop.kcl.ac.uk

First Name & Middle Initial & Last Name & Degree

Robert J Howard, MD

12. IPD Sharing Statement

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Donepezil and Memantine in Moderate to Severe Alzheimer's Disease

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