Ramanan Athimalaipet V, Dick Andrew D, Guly Catherine, McKay Andrew, Jones Ashley P, Hardwick Ben, Lee Richard W J, Smyth Matthew, Jaki Thomas, Beresford Michael W
University Hospitals Bristol NHS Foundation Trust and Bristol Medical School, University of Bristol, Bristol, UK.
Bristol Eye Hospital, Bristol, UK.
Lancet Rheumatol. 2020 Feb 7;2(3):e135-e141. doi: 10.1016/S2665-9913(20)30008-4. eCollection 2020 Mar.
Uveitis associated with juvenile idiopathic arthritis is a cause of major ocular morbidity. A substantial proportion of children are refractory to systemic methotrexate and TNF inhibitors. Our aim was to study the safety and efficacy of tocilizumab in children with juvenile idiopathic arthritis-associated uveitis refractory to both methotrexate and TNF inhibitors.
This multicentre, single-arm, phase 2 trial was done following a Simon's two-stage design at seven tertiary hospital sites in the UK. Patients aged 2-18 years with active juvenile idiopathic arthritis-associated uveitis were eligible. All patients had been on a stable dose of methotrexate for at least 12 weeks and had not responded to treatment with a TNF inhibitor. Patients weighing 30 kg or more were treated with 162 mg subcutaneous tocilizumab every 2 weeks for 24 weeks, and participants weighing less than 30 kg were treated with 162 mg every 3 weeks for 24 weeks. The primary outcome was treatment response defined as a two-step decrease, or decrease to zero, from baseline in the level of inflammation (anterior chamber cells) at week 12, per the standardisation of uveitis nomenclature criteria. A phase 3 trial would be justified if more than seven patients responded to treatment. An interim analysis was planned to assess whether the trial would be stopped for futility, with futility defined as two or fewer treatment responses among ten participants. Adverse events were collected up to 30 calendar days after treatment cessation. The primary analysis was done in the intention-to-treat population and the safety analysis was done in all patients who started the treatment. This trial is registered with the International Standard Randomised Controlled Trial Number registry (ISRCTN95363507) and EU Clinical Trials Register (EudraCT 2015-001323-23).
22 participants were enrolled to the trial between Dec 3, 2015, and March 9, 2018, and 21 participants received treatment. One participant was found to be ineligible immediately after enrolment and was therefore withdrawn. Seven of 21 (median unbiased estimate of proportion 34% [95% CI 25-57]) responded to treatment (p=0·11). Safety results were consistent with the known safety profile of tocilizumab.
The primary endpoint was not met, and thus the results do not support a phase 3 trial of tocilizumab in patients with juvenile idiopathic arthritis-associated uveitis. Importantly, data on the use of tocilizumab in clinical practice is now captured in national registries. Despite this trial not meeting the threshold required to justify a larger phase 3 trial, several patients responded to treatment; as such, tocilzumab might still be a therapeutic option in some children with uveitis refractory to anti-TNF drugs, given the absence of other treatment options.
Versus Arthritis and the National Institute for Health Research Clinical Research Network: Children.
与幼年特发性关节炎相关的葡萄膜炎是导致严重眼部疾病的一个原因。相当一部分儿童对全身用甲氨蝶呤和肿瘤坏死因子（TNF）抑制剂治疗无效。我们的目的是研究托珠单抗在对甲氨蝶呤和TNF抑制剂均无效的幼年特发性关节炎相关葡萄膜炎患儿中的安全性和有效性。
本多中心、单臂、2期试验按照西蒙两阶段设计在英国7个三级医院进行。年龄在2至18岁、患有活动性幼年特发性关节炎相关葡萄膜炎的患者符合入选标准。所有患者均已接受稳定剂量的甲氨蝶呤治疗至少12周，且对TNF抑制剂治疗无反应。体重30千克或以上的患者每2周皮下注射162毫克托珠单抗，共治疗24周；体重不足30千克的参与者每3周注射162毫克，共治疗24周。主要结局为治疗反应，根据葡萄膜炎命名标准，定义为在第12周时炎症水平（前房细胞）较基线水平下降两级或降至零。如果超过7名患者对治疗有反应，则有理由开展3期试验。计划进行中期分析以评估试验是否因无效而停止，无效定义为10名参与者中有两名或更少的治疗反应。在治疗停止后30个日历日内收集不良事件。主要分析在意向性治疗人群中进行，安全性分析在所有开始治疗的患者中进行。本试验已在国际标准随机对照试验编号注册库（ISRCTN95363507）和欧盟临床试验注册库（EudraCT 2015 - 001323 - 23）注册。
2015年12月3日至2018年3月9日期间，22名参与者入选试验，21名参与者接受了治疗。一名参与者在入选后立即被发现不符合入选标准，因此退出。21名参与者中有7名（比例的中位数无偏估计为34%[95%置信区间25 - 57]）对治疗有反应（p = 0.11）。安全性结果与托珠单抗已知的安全性特征一致。
未达到主要终点，因此结果不支持在幼年特发性关节炎相关葡萄膜炎患者中开展托珠单抗的3期试验。重要的是，托珠单抗在临床实践中的使用数据现已被纳入国家注册库。尽管本试验未达到开展更大规模3期试验所需的阈值，但仍有几名患者对治疗有反应；因此，鉴于缺乏其他治疗选择，托珠单抗可能仍是一些对抗TNF药物难治的葡萄膜炎患儿的治疗选择。
对抗关节炎组织和英国国家卫生研究院临床研究网络：儿童。
