| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| 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 |
1. To determine the clinical and cost effectiveness of two classes of antidepressants for depression in dementia (compared with placebo).
a. To determine whether an SSRI (sertraline) is i) more clinically effective and ii) more cost effective than placebo in reducing Cornell depression score 13 weeks post randomisation.
b. To determine whether an NASSA (mirtazapine) is i) more clinically effective and ii) more cost effective than placebo in reducing Cornell Depression score 13 weeks post-randomisation.
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| E.2.2 | Secondary objectives of the trial |
2. To investigate differences in the clinical and cost effectiveness, and in terms of adverse events, withdrawals from treatment and adherence to treatment between mirtazapine and sertraline for depression in dementia at 13 and 39 weeks post-randomisation.
3. To investigate differences in the clinical and cost effectiveness of mirtazapine/sertraline and placebo on patient (eg quality of life, cognition) and family carer (eg carer burden, carer quality of life) outcomes at 13 and 39 weeks post-randomisation.
4. To investigate the influence on clinical and cost effectiveness of clinical characteristics including: dementia severity, dementia type, depression type, depression severity, care arrangements, neuropsychiatric symptoms, and physical illness.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
We have designed this study as a pragmatic trial of effectiveness in routine clinical practice. We wish to minimise exclusions from the study in order to maximise the generalisability of the data generated.
The criteria for inclusion are set to be as close to clinical practice as possible. For this reason we do not specify the use of anything other than clinical diagnoses of dementia and depression since standardised instruments (other than the MMSE as a measure of severity) are not used in routine practice. A detailed characterisation of cases using standardised tools will be completed at the research assessment. We will recruit those in whom a secondary care doctor makes at the point of referral to the RW:
•a clinical diagnosis of mild to moderate probable or possible Alzheimer's Disease,
•a co-existing depressive illness likely to need treatment with antidepressants, and
•that depression should have a duration of more than four weeks.
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| E.4 | Principal exclusion criteria |
Again we wish to minimise exclusions. We will exclude from the trial those in whom a secondary care doctor finds at the point of referral to the RW are:
• currently taking antidepressants;
• those with severe dementia (defined as MMSEď‚Ł7);
• the case is considered as being too critical to be randomised (eg because of suicide risk);
• displays absolute contraindications to one or more of the trial treatments;
• they are on another trial; and
• those where there is no identifiable family carer or other informant (eg a formal/professional carer who spends sufficient time with the person with dementia to be able to give an informed opinion) to give collateral information.
We will further exclude from the trial those in whom the RW finds have:
• a Cornell score <8 at the point of randomisation
The impact of these exclusions is likely to be small with our estimate that around 10% would be excluded by reason of severity and 10% by reason of lack of identified carer. The carer exclusion is needed because our primary outcome measure, the Cornell, is a carer report instrument. However we will not require carers to be co-resident or to be providing hands-on care (many will see themselves as supporters or simply family members rather than carers per se), also information can be obtained by friends and neighbours or professional carers who take on a caring or support role.
We are not intending to exclude subjects on the basis of their taking concomitant psychotropic medication eg hypnotics, antipsychotics or cholinesterase inhibitors. These medications will be commonly prescribed in our study group and any such exclusions would limit the generalisability of the data generated, so compromising the pragmatic nature of the trial. Management of the subjects in this study will therefore mimic true clinical practice with the sole exception of the trial medication.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Depression in dementia - CSDD (Alexopoulos et al 1988)
The CSDD was designed specifically for the measurement of depression in dementia. It is widely used and well validated with acceptable reliability and feasibility. It has been shown to be responsive to change in previous trials.
Costs – Client Service Receipt Inventory (CSRI; Beecham et al 2001)
This schedule measures service use and informal care input. It allows for the comprehensive costs of care for all participants to be calculated (including the costs of formal care such as that provided by health and social services and also the costs of informal care) using data gathered from carers.
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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 | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | No |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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.8.5 | 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 | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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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| Completion of 10 months on the trial medication or withdrawal from follow-up for any cause before. Participants may withdraw from the trial medication but remain in follow-up. Participants may not formally withdraw from follow-up and remain on the trial medication. |
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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 | 2 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
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