E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Parkinson's disease with mild dementia (PDD) |
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E.1.1.1 | Medical condition in easily understood language |
Parkinson's disease with mild dementia |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Is the cholinesterase inhibitor drug donepezil hydrochloride superior to placebo in improving cognitive function, neuropsychiatric burden and functional ability in people with Parkinson’s disease and mild dementia after 24 months of treatment? |
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E.2.2 | Secondary objectives of the trial |
Is the cholinesterase inhibitor drug donepezil hydrochloride superior to placebo in improving patient and carer quality of life?
Is the use of donepezil hydrochloride cost-effective for this clinical indication?
To determine the instrument most suitable for evaluating change in cognition in people with Parkinson's disease and mild dementia.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. A diagnosis of Parkinson’s disease (PD) according to UK Parkinson's Disease Society Brain Bank Criteria. These criteria are in standard use throughout the NHS in the UK and are supported by the NICE guidelines. 2. People with mild dementia associated with PD, where the patient and/or their family has become aware of cognitive problem 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 score(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 6 (corresponding to between the 6th and 28th percentile) will be used to define "mild" dementia. 3. Community living and a spouse, close relative or well established carer to accompany the subject to act as an spokesperson. 4. Where relevant, women of child bearing potential must be using adequate contraception for the duration of study.
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E.4 | Principal exclusion criteria |
1. 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. 2. 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. 3. Severe current depressive episode. Low mood may impact upon accurate cognitive assessment and major depression is 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 (BDI) and a cut-off score of 13/14, 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. 4. Unstable significant medical co-morbidity. 5. Patient receiving an anticholinergic drug for control of parkinsonian motor symptoms. 6. Previous exposure to a cholinesterase inhibitor or contraindication to donepezil hydrochloride (including a clinically significant cardiac conduction defect). 7. Presence of a condition that is contraindicative to use of donepezil hydrochloride (including a clinically significant cardiac conduction defect found in patient history or from screening ECG) 8. Allergy/hypersensitivity to excipients of donepezil hydrochloride or placebo. 9. Patient receiving the N-methyl-d-aspartate antagonist memantine. 10. 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.
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary outcomes are changes in the Mattis Dementia Rating Scale (DRS-2), 10-item Neuropsychiatric Inventory (NPI-10) and Bristol Activity of Daily Living Scale (BADLS)deemed to be clinically meaningful. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
End of study treatment - following 7th visit (assessed during course of study participation; visit 2, 4, 5, 6 and 7 for all 3 measures and also visit 1 for the Mattis Dementia Rating Scale). |
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E.5.2 | Secondary end point(s) |
Patient quality of life (assessed using EQ5D and the DEMQOL and DEMQOL-proxy) and carer quality of life (assessed using the Scale of Quality of Life of Caregivers, which is sensitive to carer strain in PD. Data will also be collected using the Client Service Receipt Inventory for the economic evaluation of treatments, service use and carer inputs which will be turned into cost measures by applying local and national unit cost values. Quality-adjusted life years will be measured, based on the EQ5D and the DEMQOL, and these, along with other outcomes, will be employed in the cost-effectiveness analyses). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
End of study treatment - following 7th visit (assessed during course of study participation; visit 2, 4, 5, 6 and 7). |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Cost effectiveness review of scales/questionnaires for detection of changes in the patient. |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 22 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of the study will be last patient, last visit. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 30 |