A pragmatic, multicentre, double-blind, placebo-controlled randomised trial to assess the safety, clinical and cost-effectiveness of mirtazapine and carbamazepine in people with Alzheimer's disease and agitated behaviours: the HTA-SYMBAD trial.

IF 3.5 2区 医学 Q1 HEALTH CARE SCIENCES & SERVICES
Sube Banerjee, Nicolas Farina, Catherine Henderson, Juliet High, Susan Stirling, Lee Shepstone, Julia Fountain, Clive Ballard, Peter Bentham, Alistair Burns, Chris Fox, Paul Francis, Robert Howard, Martin Knapp, Iracema Leroi, Gill Livingston, Ramin Nilforooshan, Shirley Nurock, John O'Brien, Annabel Price, Alan J Thomas, Ann Marie Swart, Tanya Telling, Naji Tabet
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引用次数: 0

Abstract

Background: Agitation is common and impacts negatively on people with dementia and carers. Non-drug patient-centred care is first-line treatment, but we need other treatment when this fails. Current evidence is sparse on safer and effective alternatives to antipsychotics.

Objectives: To assess clinical and cost-effectiveness and safety of mirtazapine and carbamazepine in treating agitation in dementia.

Design: Pragmatic, phase III, multicentre, double-blind, superiority, randomised, placebo-controlled trial of the clinical effectiveness of mirtazapine over 12 weeks (carbamazepine arm discontinued).

Setting: Twenty-six UK secondary care centres.

Participants: Eligibility: probable or possible Alzheimer's disease, agitation unresponsive to non-drug treatment, Cohen-Mansfield Agitation Inventory score ≥ 45.

Interventions: Mirtazapine (target 45 mg), carbamazepine (target 300 mg) and placebo.

Outcome measures: Primary: Cohen-Mansfield Agitation Inventory score 12 weeks post randomisation. Main economic outcome evaluation: incremental cost per six-point difference in Cohen-Mansfield Agitation Inventory score at 12 weeks, from health and social care system perspective. Data from participants and informants at baseline, 6 and 12 weeks. Long-term follow-up Cohen-Mansfield Agitation Inventory data collected by telephone from informants at 6 and 12 months.

Randomisation and blinding: Participants allocated 1 : 1 : 1 ratio (to discontinuation of the carbamazepine arm, 1 : 1 thereafter) to receive placebo or carbamazepine or mirtazapine, with treatment as usual. Random allocation was block stratified by centre and residence type with random block lengths of three or six (after discontinuation of carbamazepine, two or four). Double-blind, with drug and placebo identically encapsulated. Referring clinicians, participants, trial management team and research workers who did assessments were masked to group allocation.

Results: Two hundred and forty-four participants recruited and randomised (102 mirtazapine, 102 placebo, 40 carbamazepine). The carbamazepine arm was discontinued due to slow overall recruitment; carbamazepine/placebo analyses are therefore statistically underpowered and not detailed in the abstract. Mean difference placebo-mirtazapine (-1.74, 95% confidence interval -7.17 to 3.69; p = 0.53). Harms: The number of controls with adverse events (65/102, 64%) was similar to the mirtazapine group (67/102, 66%). However, there were more deaths in the mirtazapine group (n = 7) by week 16 than in the control group (n = 1). Post hoc analysis suggests this was of marginal statistical significance (p = 0.065); this difference did not persist at 6- and 12-month assessments. At 12 weeks, the costs of unpaid care by the dyadic carer were significantly higher in the mirtazapine than placebo group [difference: £1120 (95% confidence interval £56 to £2184)]. In the cost-effectiveness analyses, mean raw and adjusted outcome scores and costs of the complete cases samples showed no differences between groups.

Limitations: Our study has four important potential limitations: (1) we dropped the proposed carbamazepine group; (2) the trial was not powered to investigate a mortality difference between the groups; (3) recruitment beyond February 2020, was constrained by the COVID-19 pandemic; and (4) generalisability is limited by recruitment of participants from old-age psychiatry services and care homes.

Conclusions: The data suggest mirtazapine is not clinically or cost-effective (compared to placebo) for agitation in dementia. There is little reason to recommend mirtazapine for people with dementia with agitation.

Future work: Effective and cost-effective management strategies for agitation in dementia are needed where non-pharmacological approaches are unsuccessful.

Study registration: This trial is registered as ISRCTN17411897/NCT03031184.

Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 23. See the NIHR Journals Library website for further project information.

一项实用、多中心、双盲、安慰剂对照的随机试验,旨在评估米氮平和卡马西平治疗阿尔茨海默病和烦躁行为患者的安全性、临床和成本效益:HTA-SYMBAD试验。
背景:激动是常见的,对痴呆症患者和护理人员产生负面影响。以非药物患者为中心的护理是一线治疗,但如果失败,我们需要其他治疗。目前关于抗精神病药物的安全有效替代品的证据很少。目的:评价米氮平和卡马西平治疗痴呆症躁动的临床疗效、成本效益和安全性。设计:米氮平临床疗效的实用、III期、多中心、双盲、优势、随机、安慰剂对照试验,为期12周(卡马西平组停用)。设置:26个英国二级护理中心。参与者:资格:可能或可能患有阿尔茨海默氏症,对非药物治疗无反应,Cohen Mansfield激动量表得分 ≥ 45.干预措施:米氮平(目标45 mg)、卡马西平(目标300 mg)和安慰剂。结果测量:主要:随机分组后12周Cohen Mansfield激动量表评分。主要经济结果评估:从卫生和社会护理系统的角度来看,Cohen Mansfield激动清单评分在12周时每6分差异的增量成本。在基线、第6周和第12周时来自参与者和线人的数据。通过电话从6个月和12个月的线人那里收集的长期随访Cohen Mansfield激动清单数据。随机分组和盲法:参与者按1:1的比例(停用卡马西平组,此后按1:1)接受安慰剂或卡马西平或米氮平,照常治疗。随机分配按中心和居住类型进行区块分层,随机区块长度为3或6(卡马西平停用后,为2或4)。双盲,药物和安慰剂封装相同。转诊临床医生、参与者、试验管理团队和进行评估的研究人员被掩盖在分组中。结果:244名参与者被招募并随机分组(102名米氮平,102名安慰剂,40名卡马西平)。卡马西平组因整体招募缓慢而停用;因此卡马西平/安慰剂分析在统计学上是不足的,并且在摘要中没有详细说明。安慰剂米氮平的平均差异(-1.74,95%置信区间-71.7-3.69;p = 危害:发生不良事件的对照组(65/102,64%)与米氮平组(67/102,66%)相似。然而,米氮平组的死亡人数更多(n = 7) 到第16周时比对照组(n = 1) 。事后分析表明,这在统计学上具有边际显著性(p = 0.065);这种差异在6个月和12个月的评估中没有持续存在。在12周时,米氮平组的二元护理人员的无偿护理费用显著高于安慰剂组[差异:1120英镑(95%置信区间为56英镑至2184英镑)]。在成本效益分析中,完整病例样本的平均原始和调整结果得分以及成本在各组之间没有差异。局限性:我们的研究有四个重要的潜在局限性:(1)我们放弃了拟议的卡马西平组;(2) 该试验无法调查两组之间的死亡率差异;(3) 2020年2月以后的招聘受到新冠肺炎大流行的限制;以及(4)由于从老年精神病服务和护理院招募参与者,普及性受到限制。结论:数据表明米氮平治疗痴呆症的躁动不具有临床或成本效益(与安慰剂相比)。没有什么理由推荐米氮平治疗伴有躁动的痴呆症患者。未来的工作:在非药物方法不成功的情况下,需要有效且具有成本效益的痴呆症躁动管理策略。研究注册:该试验注册为ISRCTN17411897/NCT0031184。资助:该项目由美国国立卫生与保健研究所(NIHR)健康技术评估计划资助,并将在《健康技术评估》上全文发表;第27卷第23期。有关更多项目信息,请访问NIHR期刊图书馆网站。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Health technology assessment
Health technology assessment 医学-卫生保健
CiteScore
6.90
自引率
0.00%
发文量
94
审稿时长
>12 weeks
期刊介绍: Health Technology Assessment (HTA) publishes research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS.
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