Coleman Kristy K L, Berry Scott, Cummings Jeffrey, Hsiung Ging-Yuek R, Laforce Robert, Huey Edward, Ducharme Simon, Tartaglia Maria Carmela, Mendez Mario F, Onyike Chiadi, Domoto-Reilly Kimiko, Masellis Mario, Herrmann Nathan, Porsteinsson Anton, Detry Michelle A, Stewart Chloe, Bosse Anna L, McGlothlin Anna, Dias Bryan, Pandey Sachin, Mayich Michael, Pasternak Stephen H, Ruiz Garcia Ramiro, Restrepo-Martinez Miguel, Feldman Howard, Boxer Adam L, Finger Elizabeth C
Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada; Department of Cognitive Neurology, St Joseph's Health Care London, London, ON, Canada.
Company Berry Consultants, Austin, TX, USA.
Lancet Neurol. 2025 Feb;24(2):128-139. doi: 10.1016/S1474-4422(24)00456-3.
No treatments exist for apathy in people with frontotemporal dementia. Previously, in a randomised double-blind, placebo-controlled, dose-finding study, intranasal oxytocin administration in people with frontotemporal dementia improved apathy ratings on the Neuropsychiatric Inventory over 1 week and, in a randomised, double-blind, placebo-controlled, crossover study, a single dose of 72 IU oxytocin increased blood-oxygen-level-dependent signal in limbic brain regions. We aimed to determine whether longer treatment with oxytocin improves apathy in people with frontotemporal dementia.
We conducted a multicentre, randomised, double-blind, placebo-controlled, adaptive, crossover, phase 2a/2b trial, enrolling participants from 11 expert frontotemporal dementia outpatient clinics across Canada and the USA. People aged 30-80 years with a diagnosis of probable frontotemporal dementia, a Neuropsychiatric Inventory apathy score of 2 or higher, a study partner who interacted with them for at least 3 h per day, and stable cognitive and behavioural medications for 30 days were eligible for inclusion. In stage 1, participants were randomly assigned (1:1:1:1:1:1) to one of three dose schedules (every day, every other day, and every third day) of 72 IU intranasal oxytocin or placebo and to the order they would received the intervention in the crossover; intranasal oxytocin or placebo were administered twice daily for 6 weeks, with a 6-week washout and then crossover to the other intervention. In stage 2, new participants were randomised (1:1) to the dose that had been determined as optimal in stage 1 or to placebo, with crossover as in stage 1. Randomisation used variable block sizes and was stratified by participant sex and Clinical Dementia Rating severity score. All kits of investigational product were identical and produced centrally, and all local teams, study staff, and participants were masked to treatment allocation and order. The primary outcome was difference in the change in Neuropsychiatric Inventory apathy scores for oxytocin versus placebo periods in the per-protocol population after 6 weeks of treatment. Safety was assessed at each visit via electrocardiogram, blood work, and collection of data on adverse events. This trial is registered at ClinicalTrials.gov (NCT03260920).
Between Jan 31, 2018, and Dec 11, 2020, 70 patients were screened for stage 1 and 60 (86%) were enrolled. 45 (75%) completed both treatment periods of stage 1. 72 IU oxytocin every third day was the optimal dose schedule from stage 1 based on its Bayesian posterior probability (Pr(Best)=0·478). Between June 28, 2021, and Jan 31, 2023, 42 patients were screened for stage 2, and 34 (81%) were enrolled. 28 (82%) completed both treatment periods in stage 2. 38 (40%) of 94 participants were female and 56 (60%) were male (mean age 65·9 years, SD 8·2) Treatment with oxytocin every third day resulted in an improved Neuropsychiatric Inventory apathy score, with an estimated -1·32 points (95% CI -2·43 to -0·21) relative to placebo (one sided p=0·010). Two adverse events were reported in at least 5% of participants: upper respiratory tract infection (five [6%] of 78 participants on placebo and three [5%] on every third day at all doses of oxytocin) and headache (two [3%] participants on placebo, one [7%] of 15 participants on oxytocin every day, and two [4%] of 55 participants on oxytocin every third day). No adverse events were attributed to oxytocin treatment.
Intranasal oxytocin given every third day was well tolerated and was associated with a small reduction in apathy in patients with frontotemporal dementia. Future trials might investigate intermittent dosing of more potent formulations than in this study, to establish whether larger effects are possible.
Canadian Institutes of Health Research and Weston Foundation.
目前尚无针对额颞叶痴呆患者冷漠症状的治疗方法。此前，在一项随机双盲、安慰剂对照的剂量探索研究中，额颞叶痴呆患者鼻内给予催产素，在1周内改善了神经精神科问卷中的冷漠评分；在一项随机、双盲、安慰剂对照的交叉研究中，单剂量72 IU催产素增加了边缘脑区的血氧水平依赖信号。我们旨在确定催产素的长期治疗是否能改善额颞叶痴呆患者的冷漠症状。
我们进行了一项多中心、随机、双盲、安慰剂对照、适应性、交叉、2a/2b期试验，从加拿大和美国的11家专业额颞叶痴呆门诊招募参与者。年龄在30-80岁之间，诊断为可能的额颞叶痴呆，神经精神科问卷冷漠评分2分或更高，有一名每天与他们互动至少3小时的研究伙伴，且认知和行为药物稳定30天的患者符合纳入标准。在第1阶段，参与者被随机分配（1:1:1:1:1:1）至三种剂量方案（每天、隔天、每三天一次）中的一种，接受72 IU鼻内催产素或安慰剂，并按交叉设计接受干预的顺序；鼻内催产素或安慰剂每天给药两次，共6周，有6周的洗脱期，然后交叉至另一种干预。在第2阶段，新参与者被随机（1:1）分配至第1阶段确定为最佳的剂量或安慰剂，交叉方式同第1阶段。随机分组采用可变块大小，并按参与者性别和临床痴呆评定严重程度评分进行分层。所有研究产品试剂盒均相同且集中生产，所有当地团队、研究人员和参与者均对治疗分配和顺序不知情。主要结局是治疗6周后，符合方案人群中催产素治疗期与安慰剂治疗期神经精神科问卷冷漠评分变化的差异。每次访视时通过心电图、血液检查和收集不良事件数据评估安全性。本试验已在ClinicalTrials.gov注册（NCT03260920）。
2018年1月31日至2020年12月11日期间，70名患者接受第1阶段筛查，60名（86%）入组。45名（75%）完成了第1阶段的两个治疗期。基于贝叶斯后验概率（Pr(Best)=0·478），每三天一次72 IU催产素是第1阶段的最佳剂量方案。2021年6月28日至2023年1月31日期间，42名患者接受第2阶段筛查，34名（81%）入组。28名（82%）完成了第2阶段的两个治疗期。94名参与者中38名（40%）为女性，56名（60%）为男性（平均年龄65·9岁，标准差8·2）。每三天一次催产素治疗使神经精神科问卷冷漠评分得到改善，相对于安慰剂估计降低了1·32分（95%置信区间-2·43至-0·21）（单侧p=0·010）。至少5%的参与者报告了两项不良事件：上呼吸道感染（安慰剂组78名参与者中有5名[6%]，所有剂量催产素每三天一次组中有3名[5%]）和头痛（安慰剂组2名[3%]参与者，每天一次催产素组15名参与者中有1名[7%]，每三天一次催产素组55名参与者中有2名[4%]）。没有不良事件归因于催产素治疗。
每三天一次鼻内给予催产素耐受性良好，且与额颞叶痴呆患者的冷漠症状小幅减轻相关。未来试验可能会研究比本研究中更有效的制剂的间歇给药，以确定是否可能产生更大的效果。
加拿大卫生研究院和韦斯顿基金会。
