Title: HTA-SYMBAD – StudY of Mirtazapine or carBamazepine for Agitation in Dementia
Funder: Department of Health and Social Care

Abstract: DESIGN Pragmatic multi-centre double-blind placebo-controlled RCT of the clinical and cost-effectiveness of mirtazapine or carbamazepine (all with usual care) at 6/12/26/52w on agitated behaviours in dementia. SETTING Community in 8 regional centres in England. TARGET POPULATION People with Alzheimer's Disease (AD) and agitated behaviours >4 weeks duration which have not responded to non-drug treatment.[1] INCLUSION/EXCLUSION CRITERIA Pragmatic trial, minimising exclusions to maximise generalisability. Inclusion: probable or possible NINDS/ADRDA Alzheimer's Disease; agitated behaviours duration >4 weeks which have not responded to the DH/AS algorithm; Cohen Mansfield Agitation Inventory (CMAI) score 45+. Exclusion: current antidepressants, anticonvulsants or antipsychotics; case too critical for randomisation; no informant to give collateral information. HEALTH TECHNOLOGIES BEING ASSESSED Experimental: Either (i) mirtazapine or (ii) carbamazepine, both with usual clinical care. Control: placebo with usual clinical care. MEASUREMENT OF COSTS AND OUTCOMES Patients and carers interviewed by research worker (RW) at 0,6&12w: Primary: (i) Agitated behaviours in dementia– CMAI. Secondary - person with dementia: (ii) Costs– Client Service Receipt Inventory (CSRI) and nationally representative unit costs;(iii) Quality of life - disease-specific-DEMQOL-Proxy and generic- EQ-5D; (iv) cognitive impairment– sMMSE; (v) Broad Behavioural and Psychological Symptoms in Dementia (BPSD)- NPI; (vi) adherence, adverse events, concomitant medication/changes, withdrawal. Secondary – carer: (vii) carer mental health– GHQ-12; (viii) carer quality of life– EQ-5D; (ix) carer burden– short form Zarit CBI; (x) carer sleep. Long term outcomes: telephone interviews at 26&52w measuring CMAI, treatment status, institutionalisation and death. Primary analyses will compare mirtazapine or carbamazepine with placebo on CMAI score change 12 weeks post randomisation. Analyses of clinical effectiveness will be pragmatic using linear mixed modelling, based on an ITT sample on all available follow-up data from all randomized patients controlling for baseline levels of agitation and centre. Secondary analyses will compare all groups and cost-effectiveness. SAMPLE SIZE An overall sample of 400 (randomised 1:1:1) provides 90% power using 2-sided 5% significance tests to detect a drug v placebo mean difference in CMAI score at 12 weeks of 6 equating to an effect size of d=0.4 (assuming a common standard deviation of 15) or a clinically significant 30% decrease in CMAI. With a realistic 15% attrition, we require a target sample of 470 (around 156 per arm). PROJECT TIMETABLES INCLUDING RECRUITMENT RATE 8 centres will each recruit 59 patients over 24 months. -6 to 0m trial approvals sought 1-6m trial systems set up 5-6m training RWs, centres set up and priming -6-6m production of trial medication and matching placebo 7-33m recruitment of patients, randomisation 8-36m follow-up interviews (6 and 12w), report preparation 30-39m final analyses and report writing, study closeout 10-45m collection of supplementary long term (24/52w) outcome data 40-48m analysis and report preparations on long term outcome data] EXPERTISE IN TEAM A broad, experienced multidisciplinary team experienced in dementia, clinical trials in dementia, statistics, health economics, implementation, policy and service user/carer perspectives.

Lay abstract: BACKGROUND Dementia causes irreversible decline in intellectual, social and physical functioning with 800,000 people affected and costs of over £20billion pa in the UK.[2,3,4] In 30 years numbers will double and costs triple.[5] Impacts on patients and carers are devastating so improving dementia care is now a national policy priority.[2,3] Behavioural and psychological symptoms in dementia (BPSD eg agitation, aggression, wandering, shouting, repeated questioning and sleep disturbance) are common occurring in up to 90% of cases.[6] Agitation, defined as inappropriate verbal, vocal or motor activity which is not an outcome of need and encompasses physical and verbal aggression,[7] is particularly problematic affecting nearly 50% of people with AD over a month.[8] 80% with clinically significant symptoms have them six months later.[9] Agitation is associated with deteriorating relationships with family and professional carers, institutionalisation, increased costs of care, distress and decreased quality of life.[9,10,11] Antipsychotics, the mainstay of drug treatment for agitation in AD, do harm. A ministerial enquiry identified that a third of people with dementia receive these drugs and they cause 1,800 deaths pa in the UK.[12] Reduction in antipsychotic use in dementia is therefore a government priority and research into safe effective alternatives is a government research priority. INTERVENTION Emerging evidence suggests two inexpensive, safe, routinely used drugs (mirtazapine, an antidepressant; carbamazepine, an anticonvulsant) may be effective in treating agitation in dementia. We propose to determine if either decreases agitation in dementia. We will carry out a trial of the effect on agitated behaviours at 6 and 12 weeks of mirtazapine or carbamazepine compared to inactive dummy capsules (placebo) and long term effects of the 12 weeks randomised treatment at 26 and 52 weeks. We will recruit 470 cases from 8 centres (59 from each); they will be allocated randomly on a 1:1:1 basis to receive either mirtazapine, carbamazepine or placebo, all with usual care. The medication will be prepared so neither researchers nor participants are aware of which they receive. SITES 8 mental health services in England. OUTCOMES Our main outcome is agitation in dementia measured by the Cohen Mansfield Agitation Inventory[13] (CMAI the best validated/most widely used measure of agitation in dementia). We will also see if the medications affect: quality of life, cognitive impairment, carers, and cost. These will be measured at baseline, 6&12w. Long term outcomes (CMAI, treatment status, institutionalisation and death) will be assessed by telephone interviews at 26&52w. ETHICAL ISSUES We have extensive experience of working with people with dementia, their carers and health providers. We will recruit people across severity of dementia; some may not have the capacity to give informed written consent. For them we will ask carers for assent; the person with dementia would only be enrolled if they showed no dissent. We will work with the Alzheimer’s Society and PPI to ensure best ethical practice. All participants will have had a trial of non-drug treatment, as set out in the DH/AS algorithm, prior to entering the trial. TEAM A broad and experienced multidisciplinary team experienced in dementia, clinical trials in dementia, statistics, health economics, implementation, policy and service user/carer perspectives.

Research activity codes: 6.1 PHARMACEUTICALS
Health categories: MENTAL HEALTH;NEUROLOGICAL