利妥昔单抗治疗儿童起病、复杂、频繁复发型肾病综合征或激素依赖型肾病综合征：一项多中心、双盲、随机、安慰剂对照试验。

Rituximab for childhood-onset, complicated, frequently relapsing nephrotic syndrome or steroid-dependent nephrotic syndrome: a multicentre, double-blind, randomised, placebo-controlled trial.

机构信息

Department of Pediatrics, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.

Division for Clinical Trials, Department of Development Strategy, Center for Social and Clinical Research, National Research Institute for Child Health and Development, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.

出版信息

Lancet. 2014 Oct 4;384(9950):1273-81. doi: 10.1016/S0140-6736(14)60541-9. Epub 2014 Jun 22.

DOI:10.1016/S0140-6736(14)60541-9

PMID:24965823

Abstract

BACKGROUND

Rituximab could be an effective treatment for childhood-onset, complicated, frequently relapsing nephrotic syndrome (FRNS) and steroid-dependent nephrotic syndrome (SDNS). We investigated the efficacy and safety of rituximab in patients with high disease activity.

METHODS

We did a multicentre, double-blind, randomised, placebo-controlled trial at nine centres in Japan. We screened patients aged 2 years or older experiencing a relapse of FRNS or SDNS, which had originally been diagnosed as nephrotic syndrome when aged 1-18 years. Patients with complicated FRNS or SDNS who met all other criteria were eligible for inclusion after remission of the relapse at screening. We used a computer-generated sequence to randomly assign patients (1:1) to receive rituximab (375 mg/m(2)) or placebo once weekly for 4 weeks, with age, institution, treatment history, and the intervals between the previous three relapses as adjustment factors. Patients, guardians, caregivers, physicians, and individuals assessing outcomes were masked to assignments. All patients received standard steroid treatment for the relapse at screening and stopped taking immunosuppressive agents by 169 days after randomisation. Patients were followed up for 1 year. The primary endpoint was the relapse-free period. Safety endpoints were frequency and severity of adverse events. Patients who received their assigned intervention were included in analyses. This trial is registered with the University Hospital Medical Information Network clinical trials registry, number UMIN000001405.

FINDINGS

Patients were centrally registered between Nov 13, 2008, and May 19, 2010. Of 52 patients who underwent randomisation, 48 received the assigned intervention (24 were given rituximab and 24 placebo). The median relapse-free period was significantly longer in the rituximab group (267 days, 95% CI 223-374) than in the placebo group (101 days, 70-155; hazard ratio: 0·27, 0·14-0·53; p<0·0001). Ten patients (42%) in the rituximab group and six (25%) in the placebo group had at least one serious adverse event (p=0·36).

INTERPRETATION

Rituximab is an effective and safe treatment for childhood-onset, complicated FRNS and SDNS.

FUNDING

Japanese Ministry of Health, Labour and Welfare.

摘要

背景

利妥昔单抗可能是治疗儿童起病、复杂、频繁复发的肾病综合征（FRNS）和激素依赖型肾病综合征（SDNS）的有效方法。我们研究了利妥昔单抗在高疾病活动度患者中的疗效和安全性。

方法

我们在日本的 9 个中心进行了一项多中心、双盲、随机、安慰剂对照试验。我们筛选了年龄在 2 岁及以上、经历 FRNS 或 SDNS 复发的患者，这些患者在 1-18 岁时被诊断为肾病综合征。符合所有其他标准的复杂 FRNS 或 SDNS 患者在筛选时复发缓解后有资格入选。我们使用计算机生成的序列将患者（1:1）随机分配接受利妥昔单抗（375mg/m²）或安慰剂，每周一次，共 4 周，调整因素为年龄、机构、治疗史以及前三次复发之间的间隔。患者、监护人、护理人员、医生和评估结果的人员对分组均不知情。所有患者在筛选时接受标准的激素治疗来治疗复发，并在随机分组后 169 天内停止使用免疫抑制剂。患者随访 1 年。主要终点是无复发期间。安全性终点为不良事件的频率和严重程度。接受指定干预的患者纳入分析。本试验在大学医院医疗信息网临床试验注册中心注册，编号 UMIN000001405。

结果

患者于 2008 年 11 月 13 日至 2010 年 5 月 19 日期间在中心注册。52 名接受随机分组的患者中，有 48 名接受了指定的干预措施（24 名接受利妥昔单抗，24 名接受安慰剂）。利妥昔单抗组的中位无复发期明显长于安慰剂组（267 天，95%CI 223-374）（101 天，70-155；风险比：0.27，0.14-0.53；p<0.0001）。利妥昔单抗组 10 名患者（42%）和安慰剂组 6 名患者（25%）至少发生 1 次严重不良事件（p=0.36）。