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

March 19, 2009 updated by: King's College London

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:

  1. 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.
  2. 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.
  3. 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.

Study Overview

Status

Unknown

Conditions

Intervention / 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.

Study Type

Interventional

Enrollment (Anticipated)

800

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
      • London, United Kingdom, SE5 8AF
        • Recruiting
        • Institute of Psychiatry
        • Contact:
        • Principal Investigator:
          • Robert J Howard, MD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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:

  1. SMMSE = 5 to 13 (13 chosen as NICE threshold of 10 plus 1 SD on SMMSE score)
  2. Continuously prescribed donepezil for at least 3 months
  3. Maintained on 10mg donepezil in previous 6 weeks.
  4. No changes in prescription of any psychotropic (antipsychotic, antidepressant, benzodiazepine) medication in previous 6 weeks.
  5. 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.
  6. Patient is community resident and has family or professional carer or is visited on at least a daily basis by carer.
  7. Patient agrees to participate if considered capable (see section 7.5)
  8. 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:

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Factorial Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: 1

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
Other Names:
  • Ebixa
Drug: Donepezil
10mg donepezil
Other Names:
  • Aricept
Placebo Comparator: 2

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
Other Names:
  • Ebixa
Drug: Placebo donepezil
Placebo donepezil
Placebo Comparator: 3

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
Other Names:
  • Aricept
Drug: Placebo memantine
Placebo memantine
Placebo Comparator: 4

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Cognitive Function measured with the Standardised MMSE (SMMSE).
Time Frame: 4 years
4 years
Activities of Daily Living measured with the Bristol Activities of Daily Living scale (BADLS).
Time Frame: 4 years
4 years

Secondary Outcome Measures

Outcome Measure
Time Frame
Non-cognitive dementia symptoms measured with the Neuropsychiatric Inventory (NPI) and the Cohen-Mansfield Agitation Inventory.
Time Frame: 4 years
4 years
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
4 years
Care-giver burden measured with the General Health Questionnaire.
Time Frame: 4 years
4 years
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
4 years
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
4 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

King's College London

Investigators

  • Principal Investigator: Robert J Howard, MD, Institute of Psychiatry

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

February 1, 2008

Primary Completion (Anticipated)

February 1, 2012

Study Completion (Anticipated)

June 1, 2013

Study Registration Dates

First Submitted

March 19, 2009

First Submitted That Met QC Criteria

March 19, 2009

First Posted (Estimate)

March 20, 2009

Study Record Updates

Last Update Posted (Estimate)

March 20, 2009

Last Update Submitted That Met QC Criteria

March 19, 2009

Last Verified

March 1, 2009

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2006/123
  • ISRCTN49545035
  • Eudract 2007-001172-36

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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