Multi-centre UK Study of the Acetylcholinesterase Inhibitor Donepezil in Early Dementia Associated With Parkinson's Disease

Study Overview
=================
Brief Summary
-----------------
To demonstrate the superiority of donepezil over placebo in improving cognitive function, neuropsychiatric burden and functional ability in people with Parkinson's disease and mild dementia after 24 months of treatment. To demonstrate the superiority of donepezil over placebo in improving patient and carer quality of life and to establish the cost-effectiveness of donepezil. To determine the instrument most suitable for evaluating change in cognition in people with Parkinson's disease and mild dementia.

Official Title
-----------------
Multi-centre UK Study of the Acetylcholinesterase Inhibitor Donepezil in Early Dementia Associated With Parkinson's Disease

Conditions
-----------------
Parkinson's Disease

Intervention / Treatment
-----------------
* Drug: Donepezil


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: A diagnosis of Parkinson's disease according to UK Parkinson's Disease Society Brain Bank Criteria. These criteria are in standard use throughout the NHS in the UK and were supported by the NICE guidelines. People with mild dementia associated with PD, where the patient and/or their family have become aware of cognitive with or without behavioural symptoms that are causing functional impairment. Dementia will be defined according to recently published Movement Disorder Society Task Force criteria for dementia associated with Parkinson's Disease and operationalised using the Addenbrooke's Cognitive Examination (ACE-R). The ACE-R permits some description of the dementia profile and also quantifies global impairment. It is increasingly used by clinicians in the UK to identify demented subjects, is relatively quick to perform (15 minutes or so), requires no specific training and produces a total score (0-100), from which the MMSE (0-30) can also be extracted. Participants will have an ACE-R of 88 or less. If this criterion is met, subjects will be further assessed using the Mattis Dementia Rating Scale (DRS-2). An age- and education-corrected total DRS-2 score of less than 8 but greater than 4 (corresponding to between the 6th and 28th percentile) will be used to define mild dementia. Community-living and a spouse, close relative or well established carer to accompany the subject to act as an informant. Where relevant, women of child bearing potential must be using adequate contraception for duration of study. Exclusion Criteria: Dementia that develops within one year of the onset of motor symptoms. The reason for this one year rule is to specifically exclude participants with Dementia with Lewy Bodies (DLB). This exclusion criterion is consistent with recommendations made in the Movement Disorder Society Dementia Task Force Diagnostic Criteria and the Third Report of the DLB Consortium. People with such severe motor disability, or who are so impaired in their activities of daily living from other aspects of their PD, that it would interfere with cognitive and global assessments. Severe current depressive episode. Low mood may impact upon accurate cognitive assessment and major depression is therefore listed as a feature which, when present, makes it impossible to reliably diagnose PDD in the Movement disorder Society Task Force PDD Criteria. This will be operationalised using the self-completed Beck Depression Inventory and a cut-off score of 13, as recommended by a recent Movement Disorder Society Task Force report. The BDI score is considered robust in the face of mild to moderate cognitive impairment. Unstable significant medical co-morbidity. Patient receiving an anticholinergic drug for control of parkinsonian motor symptoms. Previous exposure to a cholinesterase inhibitor Presence of a condition that is contraindicative to use of donepezil (including a clinically significant cardiac conduction defect found in patient history or from screening ECG); see SmPC (Appendix W) for details. Allergy/hypersensitivity to excipients of donepezil or placebo Patient receiving the N-methyl-d-aspartate antagonist memantine. Previous neurosurgery for Parkinson's disease. This will apply to only a small minority of predominantly younger cases. The main reason for this exclusion relates to ongoing uncertainty over the potential confounding effects of deep brain stimulation upon both mood and cognition.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Donepezil<br>5mg of Donepezil for the first 8 weeks raising to 10mg thereafter if patient adjusted to 5mg dose. 10mg does continues for the remainder of the study. | Drug: Donepezil<br>* 5mg donepezil daily for first 8 weeks and then increased to 10mg daily for the remainder of the study.<br>|
| Placebo Comparator: Placebo<br>Patient commences medication to match appearance of 5mg donepezil for first 8 weeks then 10mg for the remainder of the study. | Drug: Donepezil<br>* 5mg donepezil daily for first 8 weeks and then increased to 10mg daily for the remainder of the study.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To demonstrate the superiority of donepezil over placebo in improving cognitive function, neuropsychiatric burden and functional ability in people with Parkinson's disease and mild dementia after 24 months of treatment. |  | After 24 month of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To demonstrate the superiority of donepezil over placebo in improving patient and carer quality of life and to establish the cost-effectiveness of donepezil. |  | 26, 52 and 104 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Parkinson's disease, mild dementia, donepezil, NIHR HTA