The Dementia Study in Northern Norway



The Dementia Study in Northern Norway

Registration:

EudraCTNR. 2004-002613-37. (Identifier: NCT00443014).

Revised 29th December 2009

The Department of Community medicine,

University of Tromsø, Norway

January 2006 – June 2009

Project leader: Fred Andersen MD

Scientific supervisor:

Torgeir Engstad, Associated professor, Department of Geriatric, University Hospital in Northern Norway, Tromsø

Scientific advisory board:

Bjørn Straume, Associated professor, Department of Community Medicine, University of Tromsø

Matti Viitanen Professor, Department of Geriatrics, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden, and University of Turku, Turku, Finland

Dag Seeger Halvorsen MD PhD Department of Medicine, University Hospital in Northern Norway, Tromsø

Rolf Salvesen Professor, Department of Neurology, County Hospital in Nordland, Bodø

Content:

1. Summary

2. Background

3. Hypothesis

3.1Main purpose

2. Secondary purpose

4. Method

1. Participants

2. Diagnostic criteria

3. Diagnosing dementia in the community

4. Inclusion criteria

5. Exclusion criteria

6. Consent

7. Basic recording file

8. Intervention

9. Randomisation

4.10 Outcomes

4.11Test for reliability

4.12 Follow up

4.13 Study phases

5. Protocol extension

5.1 Screening and examination

5.2 Biobank and cognitively healthy control group

6. Ethical considerations

6.1 Consent competence

6.2 Study design

6.3 Approvals

7. Statistics

7.1 Main analyses

7.2 Power

8. Data

8.1 Data collection and security

8.2 Ownership and conflicts of interest

9. Administration

9.1 Funding

9.3 Officers in charge

9.4 Monitoring

1. Summary

This study has a two-by-two factorial design and is run on municipality level. The main purpose of the study is to examine the effect of stimulation therapy on cognitive function among community dwellers in Northern Norway with a resent diagnosis of mild to moderate Alzheimer’s disease (AD). A secondary purpose is to examine whether donepezil has an additional effect on cognition when added to stimulation therapy. 200 participants are expected to be included from nine municipalities during two years. In five municipalities the participants receive structured stimulation therapy, and in the remaining four they receive standard care, the latter acting as a control group. In both municipality groups participants are randomised double blinded to donepezil or placebo. Individuals with memory complaints are examined and diagnosed by general practitioners (GPs). Having received written and verbal information individuals with a diagnosis of probable AD are invited to participate in the study. Those willing to participate are then asked to sign a consent statement before they are included into the study. After inclusion each patient is examined with validated cognitive and neuropsychiatric tests every four months during a 1-year follow-up. The stimulation therapy offered to the five interventional municipalities consists of a wide range of individually adjusted activities. In the four control municipalities the participants receive standard care. All participants receive donepezil or placebo in a random and double blinded manner.

2. Background

Alzheimer’s disease (AD), constituting 65-70% of all dementia subtypes, is an age related progressive neurodegenerative disorder with increasing cognitive disability and impaired activities of daily living. The crude prevalence of dementia increases in Norway as elsewhere in the western countries1. Dementia imposes an increasing social and economic burden on the society. Any treatment aimed to reduce or reverse disease progress or postpone cognitive deterioration will be demanded by those afflicted, the caregivers and the society2.

Stimulation therapy like physical exercise3;4, occupational therapy, cognitive and social stimulation5;6 has been applied in a number of studies with different design and duration7. The efficacy of stimulation therapy has not been convincing, and some of the studies report contradictory results. A Cochrane review 2003 found no effect of single cognitive stimulation therapy8. However, a meta-analysis of 30 trials studying the effect of exercise training in AD patients showed a significant effect on cognitive and functional performance as compared to a control group receiving standard care9. Graff et al. showed that occupational therapy improved cognitive function significantly and reduced the burden on caregivers10.

In research stimulation therapy is challenging methodologically. Double blinding is impossible, whereas single blinding of test technicians is an option, but not always reliable. The interventional methods are time- and resource consuming and require programs of education and training to health professionals and caregivers. As a consequence studies comprising stimulation therapy usually have small sample size and relatively short duration. The number of weekly stimulation sessions has also been limited. Standardised and validated programs of stimulation therapy are not yet available. These methodological challenges reduce the accuracy and precision of any interventional study using stimulation therapy. However, a number of small interventional studies have been accomplished during the last years, most of them reporting significant effect of stimulation therapy compared to control groups. The effect of long lasting stimulation therapy on AD is still lacking.

The drug treatment, which is symptomatic, has the last 15 years focused on insufficient neurotransmission, and mainly on cholinergic and glutamate synapses. During the recent years more attention is paid to reduced multisynaptic interactions affecting different cognitive domains like memory, attention and learning. A number of new drugs have been synthesized and tested, but only a few have provided symptomatic effect and proven to be safe enough for clinical application. In Norway three members of the cholinesterase inhibitors (ChEI) have received legal marketing for symptomatic treatment of early stage AD, of which donepezil is used most frequently. The safety and efficacy of these drugs have been discussed for years. The clinical trials of ChEI launched prior to approve marketing (Phase II and III studies) were of short duration, usually between 12 and 24 weeks11. These studies have been succeeded by a number of Phase IV studies, some of them lasting for a couple of years12. One of the largest population based ChEI studies included 595 AD patients and lasted for more than one year (AD2000)13. An increase in MMSE sum score of 0.8 points by donepezil as compared to placebo was reported (p ................
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