Deferiprone in Alzheimer Disease: A Randomized Clinical Trial.

IF 20.4 1区 医学 Q1 CLINICAL NEUROLOGY JAMA neurology Pub Date : 2024-11-04 DOI:10.1001/jamaneurol.2024.3733
Scott Ayton, David Barton, Bruce Brew, Amy Brodtmann, Roger Clarnette, Patricia Desmond, David Devos, Kathryn A Ellis, Amir Fazlollahi, Caroline Fradette, Anita M Y Goh, Pawel Kalinowski, Christopher Kyndt, Rosalyn Lai, Yen Ying Lim, Paul Maruff, Terence J O'Brien, Christopher Rowe, Olivier Salvado, Peter W Schofield, Michael Spino, Fernando Tricta, Aaron Wagen, Robert Williams, Michael Woodward, Ashley I Bush
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Abstract

Importance: Interventions that substantially slow neurodegeneration are needed to address the growing burden of Alzheimer disease (AD) to societies worldwide. Elevated brain iron observed in AD has been associated with accelerated cognitive decline and may be a tractable drug target.

Objective: To investigate whether the brain-permeable iron chelator deferiprone slows cognitive decline in people with AD.

Design, setting, and participants: This phase 2, double-masked, placebo-controlled randomized clinical trial of 12-month duration was conducted at 9 sites in Australia between August 2, 2018, and April 1, 2023. Patients older than 54 years with amyloid-confirmed mild cognitive impairment or early AD (a Mini-Mental State Examination score of 20 or higher) were screened. Randomization was 2:1 and masked to participants and all study staff.

Interventions: Deferiprone 15 mg/kg twice a day or placebo administered orally for 12 months.

Main outcomes and measures: The primary outcome was a composite cognitive measure assessed at baseline, 6 months, and 12 months using a neuropsychological test battery (NTB) of memory, executive function, and attention tasks. Secondary outcomes included change in brain iron burden measured by quantitative susceptibility mapping (QSM) magnetic resonance imaging (target engagement), brain volume changes (secondary efficacy measure), and adverse events (safety analysis).

Results: Of 167 patients screened for eligibility, 81 were included, with 53 randomly assigned to the deferiprone group (mean [SD] age, 73.0 [8.0] years; 29 male [54.7%]) and 28 to the placebo group (mean [SD] age, 71.6 [7.2] years; 17 male [60.7%]); 54 participants completed the study (7 [25.0%] withdrew from the placebo group and 20 [37.7%] from the deferiprone group). In an intention-to-treat analysis, participants in the deferiprone group showed accelerated cognitive decline on the NTB primary outcome (β for interaction = -0.50; 95% CI, -0.80 to -0.20) compared with placebo (change in NTB composite z score for deferiprone, -0.80 [95% CI, -0.98 to -0.62]; for placebo, -0.30 [95% CI, -0.54 to -0.06]). Secondary analysis revealed that this result was driven by worsening performance on executive function tests. The QSM confirmed that deferiprone decreased iron in the hippocampus compared with placebo (change in hippocampal QSM for deferiprone, -0.36 ppb [95% CI, -0.76 to 0.04 ppb]; for placebo, 0.32 ppb [95% CI, -0.12 to 0.75 ppb]; β for interaction = -0.68 [95% CI, -1.27 to -0.09]). Longitudinal hippocampal volume loss was not affected by deferiprone, but exploratory analysis of other brain regions revealed increased volume loss with deferiprone in frontal areas. The frequency of the adverse effect of neutropenia (4 participants [7.5%] in the deferiprone group) was higher than in similar studies (1.6%-4.4%).

Conclusions: These trial findings show that deferiprone 15 mg/kg twice a day decreased hippocampal QSM and accelerated cognitive decline in patients with amyloid-confirmed early AD, suggesting that lowering iron with deferiprone is detrimental to patients with AD.

Trial registration: ClinicalTrials.gov Identifier: NCT03234686.

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去铁酮治疗阿尔茨海默病:随机临床试验
重要性:要解决阿尔茨海默病(AD)给全球社会带来的日益沉重的负担,就需要采取能大幅减缓神经退行性变的干预措施。在阿尔茨海默病中观察到的脑铁升高与认知能力的加速衰退有关,这可能是一个可行的药物靶点:目的:研究脑渗透性铁螯合剂去铁酮是否能减缓AD患者的认知能力衰退:这项为期12个月的2期、双掩蔽、安慰剂对照随机临床试验于2018年8月2日至2023年4月1日期间在澳大利亚的9个地点进行。54岁以上、经淀粉样蛋白证实患有轻度认知障碍或早期AD(迷你精神状态检查评分20分或更高)的患者接受了筛选。随机分配比例为2:1,并对参与者和所有研究人员进行蒙蔽:干预措施:口服去铁酮15毫克/千克,每天两次,或口服安慰剂,为期12个月:主要结果是在基线、6个月和12个月时使用神经心理测试电池(NTB)评估记忆、执行功能和注意力任务的综合认知测量。次要结果包括通过定量易感性图谱(QSM)磁共振成像测量的脑铁负荷变化(目标参与)、脑容量变化(次要疗效测量)和不良事件(安全性分析):在通过资格筛查的167名患者中,81人被纳入研究,其中53人被随机分配到去铁酮组(平均[标码]年龄为73.0[8.0]岁;29名男性[54.7%]),28人被分配到安慰剂组(平均[标码]年龄为71.6[7.2]岁;17名男性[60.7%]);54人完成了研究(7人[25.0%]退出安慰剂组,20人[37.7%]退出去铁酮组)。在意向治疗分析中,与安慰剂相比,去铁酮组参与者在NTB主要结果上的认知能力下降速度加快(交互作用β=-0.50;95% CI,-0.80至-0.20)(去铁酮的NTB综合Z评分变化为-0.80 [95% CI,-0.98至-0.62];安慰剂为-0.30 [95% CI,-0.54至-0.06])。二次分析表明,这一结果是由执行功能测试成绩的恶化引起的。QSM证实,与安慰剂相比,去铁酮能减少海马中的铁(去铁酮的海马QSM变化为-0.36 ppb [95% CI, -0.76 to 0.04 ppb];安慰剂为0.32 ppb [95% CI, -0.12 to 0.75 ppb];交互作用的β = -0.68 [95% CI, -1.27 to -0.09])。去铁酮对纵向海马体积损失没有影响,但对其他脑区的探索性分析表明,去铁酮会增加额叶区的体积损失。中性粒细胞减少症这一不良反应的发生率(去铁酮组4人[7.5%])高于类似研究(1.6%-4.4%):这些试验结果表明,去铁酮15毫克/千克,每天两次,可降低淀粉样蛋白确诊的早期AD患者的海马QSM,并加速其认知能力下降,这表明去铁酮降铁对AD患者不利:试验注册:ClinicalTrials.gov Identifier:试验注册:ClinicalTrials.gov Identifier:NCT03234686。
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
JAMA neurology
JAMA neurology CLINICAL NEUROLOGY-
CiteScore
41.90
自引率
1.70%
发文量
250
期刊介绍: JAMA Neurology is an international peer-reviewed journal for physicians caring for people with neurologic disorders and those interested in the structure and function of the normal and diseased nervous system. The Archives of Neurology & Psychiatry began publication in 1919 and, in 1959, became 2 separate journals: Archives of Neurology and Archives of General Psychiatry. In 2013, their names changed to JAMA Neurology and JAMA Psychiatry, respectively. JAMA Neurology is a member of the JAMA Network, a consortium of peer-reviewed, general medical and specialty publications.
期刊最新文献
Deferiprone in Alzheimer Disease: A Randomized Clinical Trial. Immediate or Delayed Statin in Acute Atherosclerotic Ischemia. Immediate or Delayed Statin in Acute Atherosclerotic Ischemia-Reply. Remembering the Physician's Humanity-Physicians Are Humans Too. Alzheimer Disease as a Clinical-Biological Construct-An International Working Group Recommendation.
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