共济失调毛细血管扩张症儿童红细胞内地塞米松磷酸钠(ATTeST)的安全性和有效性:一项多中心、随机、双盲、安慰剂对照的第 3 期试验。

IF 46.5 1区 医学 Q1 CLINICAL NEUROLOGY Lancet Neurology Pub Date : 2024-09-01 DOI:10.1016/S1474-4422(24)00220-5
Stefan Zielen, Thomas Crawford, Luca Benatti, Mauro Magnani, Matthias Kieslich, Monique Ryan, Isabelle Meyts, Sheffali Gulati, Rupam Borgohain, Ravi Yadav, Pramod Pal, Anaita Hegde, Suresh Kumar, Anand Venkateswar, Vrajesh Udani, Kollencheri P Vinayan, Andreea Nissenkorn, Elisa Fazzi, Vincenzo Leuzzi, Asbjørg Stray-Pedersen, Barbara Pietrucha, Samuel I Pascual, Riadh Gouider, Mary Kay Koenig, Steve Wu, Susan Perlman, Dirk Thye, Guenter Janhofer, Biljana Horn, William Whitehouse, Howard Lederman
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Participants were randomly assigned (1:1:1) to low-dose (approximately 5-10 mg), or high-dose (approximately 14-22 mg) intra-erythrocyte dexamethasone sodium phosphate, or placebo, using an independent interactive web response system, with minimisation for sex and age (6-9 years vs ≥10 years). Intravenous intra-erythrocyte dexamethasone sodium phosphate was administered once a month for 6 months. Participants, employees of the sponsor, investigators, all raters of efficacy endpoints, and central reviewers were masked to treatment assignment and dose allocations. The primary efficacy endpoint was change in the modified International Cooperative Ataxia Rating Scale (mICARS) from baseline to month 6, assessed in the modified intention-to-treat (mITT) population, which included all randomly assigned participants who received at least one dose of study drug and had at least one post-baseline efficacy assessment. 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Adverse events were reported in 43 (73%) of 59 participants in the low-dose group, 47 (82%) of 57 participants in the high-dose group, and 43 (73%) of 59 participants in the placebo group. Serious adverse events were observed in six (10%) of 59 participants in the low-dose group, seven (12%) of 57 participants in the high-dose group, and seven (12%) of 59 participants in the placebo group. There were no reports of hyperglycaemia, hypertension, hirsutism, or Cushingoid appearance in any of the treatment groups, nor any treatment-related deaths.</p><p><strong>Interpretation: </strong>Although there were no safety concerns, the primary efficacy endpoint was not met, possibly related to delays in treatment reducing the number of participants who received treatment as outlined in the protocol, and potentially different treatment effects according to age. 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引用次数: 0

摘要

背景介绍共济失调毛细血管扩张症是一种进行性神经变性的多系统疾病。皮质类固醇可改善该疾病患者的神经功能,但肾上腺抑制和停药后症状复发限制了皮质类固醇的使用,这促使人们开发新型类固醇给药系统。ATTeST研究的目的是评估在共济失调毛细血管扩张症儿童中红细胞内给药地塞米松磷酸钠与安慰剂相比的疗效和安全性:这项多中心、随机、双盲、安慰剂对照的 3 期试验在 12 个国家(澳大利亚、比利时、德国、印度、以色列、意大利、挪威、波兰、西班牙、突尼斯、英国和美国)的 22 个中心进行。符合条件的参与者为 6 岁或以上、体重超过 15 千克、符合共济失调毛细血管扩张症临床标准但自主步态得以保留的儿童。采用独立的交互式网络响应系统,将参与者随机分配(1:1:1)到低剂量(约 5-10 毫克)或高剂量(约 14-22 毫克)红细胞内地塞米松磷酸钠或安慰剂中,并将性别和年龄(6-9 岁与≥10 岁)最小化。红细胞内静脉注射地塞米松磷酸钠,每月一次,持续 6 个月。参与者、申办方员工、研究人员、疗效终点的所有评定者和中央审查员均被蒙蔽,不知道治疗分配和剂量分配。主要疗效终点是改良的国际共济失调合作评定量表(mICARS)从基线到第6个月的变化,在改良的意向治疗(mITT)人群中进行评估,该人群包括所有随机分配的参与者,他们至少接受了一个剂量的研究药物,并至少进行了一次基线后疗效评估。该试验已在Clinicaltrials.gov(NCT02770807)注册,并已完成:2017年3月2日至2021年5月13日期间,239名儿童接受了资格评估,其中176人被随机分配。一名被分配到大剂量红细胞内地塞米松磷酸钠治疗的患者没有开始治疗。175名患者接受了至少一个剂量的治疗(59名患者接受了低剂量红细胞内地塞米松磷酸钠治疗,57名患者接受了高剂量红细胞内地塞米松磷酸钠治疗,59名患者接受了安慰剂治疗)。mITT人群包括164名参与者(低剂量组56名儿童、高剂量组54名儿童和安慰剂组54名儿童)。与安慰剂组相比,低剂量组(最小平方均差-1-37 [95% CI -2-932 to 0-190])或高剂量组(-1-40 [-2-957 to 0-152];P=0-0765)mICARS评分从基线到6个月的变化无差异。低剂量组 59 名参与者中有 43 人(73%)、高剂量组 57 名参与者中有 47 人(82%)、安慰剂组 59 名参与者中有 43 人(73%)报告了不良事件。低剂量组 59 名参与者中有 6 人(10%)、高剂量组 57 名参与者中有 7 人(12%)、安慰剂组 59 名参与者中有 7 人(12%)出现严重不良反应。各治疗组均未出现高血糖、高血压、多毛症或库欣样体征,也未出现与治疗相关的死亡病例:虽然没有安全问题,但主要疗效终点没有达到,这可能与治疗延迟减少了按照方案接受治疗的参与者人数有关,也可能与不同年龄的治疗效果不同有关。根据该试验的亚组分析结果,将继续对6-9岁的参与者进行红细胞内给药地塞米松磷酸钠的研究:EryDel 和 Quince Therapeutics。
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Safety and efficacy of intra-erythrocyte dexamethasone sodium phosphate in children with ataxia telangiectasia (ATTeST): a multicentre, randomised, double-blind, placebo-controlled phase 3 trial.

Background: Ataxia telangiectasia is a multisystem disorder with progressive neurodegeneration. Corticosteroids can improve neurological functioning in patients with the disorder but adrenal suppression and symptom recurrence on treatment discontinuation has limited their use, prompting the development of novel steroid delivery systems. The aim of the ATTeST study was to evaluate the efficacy and safety of intra-erythrocyte delivery of dexamethasone sodium phosphate compared with placebo in children with ataxia telangiectasia.

Methods: This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 22 centres in 12 countries (Australia, Belgium, Germany, India, Israel, Italy, Norway, Poland, Spain, Tunisia, the UK, and the USA). Eligible participants were children aged 6 years or older weighing more than 15 kg who met clinical criteria for ataxia telangiectasia but who had preserved autonomous gait. Participants were randomly assigned (1:1:1) to low-dose (approximately 5-10 mg), or high-dose (approximately 14-22 mg) intra-erythrocyte dexamethasone sodium phosphate, or placebo, using an independent interactive web response system, with minimisation for sex and age (6-9 years vs ≥10 years). Intravenous intra-erythrocyte dexamethasone sodium phosphate was administered once a month for 6 months. Participants, employees of the sponsor, investigators, all raters of efficacy endpoints, and central reviewers were masked to treatment assignment and dose allocations. The primary efficacy endpoint was change in the modified International Cooperative Ataxia Rating Scale (mICARS) from baseline to month 6, assessed in the modified intention-to-treat (mITT) population, which included all randomly assigned participants who received at least one dose of study drug and had at least one post-baseline efficacy assessment. This trial is registered with Clinicaltrials.gov (NCT02770807) and is complete.

Findings: Between March 2, 2017, and May 13, 2021, 239 children were assessed for eligibility, of whom 176 were randomly assigned. One patient assigned to high-dose intra-erythrocyte dexamethasone sodium phosphate did not initiate treatment. 175 patients received at least one dose of treatment (59 patients received the low dose and 57 received the high dose of intra-erythrocyte dexamethasone sodium phosphate, and 59 received placebo). The mITT population comprised 164 participants (56 children in the low-dose group, 54 children in the high-dose group, and 54 in the placebo group). Compared with the placebo group, no differences were identified with regard to change in mICARS score from baseline to 6 months in the low-dose group (least squares mean difference -1·37 [95% CI -2·932 to 0·190]) or the high-dose group (-1·40 [-2·957 to 0·152]; p=0·0765). Adverse events were reported in 43 (73%) of 59 participants in the low-dose group, 47 (82%) of 57 participants in the high-dose group, and 43 (73%) of 59 participants in the placebo group. Serious adverse events were observed in six (10%) of 59 participants in the low-dose group, seven (12%) of 57 participants in the high-dose group, and seven (12%) of 59 participants in the placebo group. There were no reports of hyperglycaemia, hypertension, hirsutism, or Cushingoid appearance in any of the treatment groups, nor any treatment-related deaths.

Interpretation: Although there were no safety concerns, the primary efficacy endpoint was not met, possibly related to delays in treatment reducing the number of participants who received treatment as outlined in the protocol, and potentially different treatment effects according to age. Studies of intra-erythrocyte delivery of dexamethasone sodium phosphate will continue in participants aged 6-9 years, on the basis of findings from subgroup analyses from this trial.

Funding: EryDel and Quince Therapeutics.

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来源期刊
Lancet Neurology
Lancet Neurology 医学-临床神经学
CiteScore
58.70
自引率
1.00%
发文量
572
审稿时长
6-12 weeks
期刊介绍: The Lancet Neurology is the world-leading clinical neurology journal. It publishes original research that advocates for change in, or sheds light on, neurological clinical practice. The topics covered include cerebrovascular disease, Alzheimer's disease and other dementias, epilepsy, migraine, neurological infections, movement disorders, multiple sclerosis, neuromuscular disorders, peripheral nerve disorders, pediatric neurology, sleep disorders, and traumatic brain injury. The journal publishes a range of article types, including Articles (including randomized clinical trials and meta-analyses), Review, Rapid Review, Comment, Correspondence, and Personal View. It also publishes Series and Commissions that aim to shape and drive positive change in clinical practice and health policy in areas of need in neurology. The Lancet Neurology is an internationally trusted source of clinical, public health, and global health knowledge. It has an Impact Factor of 48.0, making it the top-ranked clinical neurology journal out of 212 journals worldwide.
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