BACKGROUND Transfusion-dependent haemoglobinopathies require lifelong iron chelation therapy with one of the three iron chelators (deferiprone, deferasirox, or deferoxamine). Deferasirox and deferiprone are the only two oral chelators used in adult patients with transfusion-dependent haemoglobinopathies. To our knowledge, there are no randomised clinical trials comparing deferiprone, a less expensive iron chelator, with deferasirox in paediatric patients. We aimed to show the non-inferiority of deferiprone versus deferasirox. METHODS DEEP-2 was a phase 3, multicentre, randomised trial in paediatric patients (aged 1 month to 18 years) with transfusion-dependent haemoglobinopathies. The study was done in 21 research hospitals and universities in Italy, Egypt, Greece, Albania, Cyprus, Tunisia, and the UK. Participants were receiving at least 150 mL/kg per year of red blood cells for the past 2 years at the time of enrolment, and were receiving deferoxamine (<100 mg/kg per day) or deferasirox (<40 mg/kg per day; deferasirox is not registered for use in children aged <2 years so only deferoxamine was being used in these patients). Any previous chelation treatment was permitted with a 7-day washout period. Patients were randomly assigned 1:1 to receive orally administered daily deferiprone (75-100 mg/kg per day) or daily deferasirox (20-40 mg/kg per day) administered as dispersible tablets, both with dose adjustment for 12 months, stratified by age (<10 years and ≥10 years) and balanced by country. The primary efficacy endpoint was based on predefined success criteria for changes in serum ferritin concentration (all patients) and cardiac MRI T2-star (T2*; patients aged >10 years) to show non-inferiority of deferiprone versus deferasirox in the per-protocol population, defined as all randomly assigned patients who received the study drugs and had available data for both variables at baseline and after 1 year of treatment, without major protocol violations. Non-inferiority was based on the two-sided 95% CI of the difference in the proportion of patients with treatment success between the two groups and was shown if the lower limit of the two-sided 95% CI was greater than -12·5%. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with EudraCT, 2012-000353-31, and ClinicalTrials.gov, NCT01825512. FINDINGS 435 patients were enrolled between March 17, 2014, and June 16, 2016, 393 of whom were randomly assigned to a treatment group (194 to the deferiprone group; 199 to the deferasirox group). 352 (90%) of 390 patients had β-thalassaemia major, 27 (7%) had sickle cell disease, five (1%) had thalassodrepanocytosis, and six (2%) had other haemoglobinopathies. Median follow-up was 379 days (IQR 294-392) for deferiprone and 381 days (350-392) for deferasirox. Non-inferiority of deferiprone versus deferasirox was established (treatment success in 69 [55·2%] of 125 patients assigned deferiprone with primary composite efficacy endpoint data available at baseline and 1 year vs 80 [54·8%] of 146 assigned deferasirox, difference 0·4%; 95% CI -11·9 to 12·6). No significant difference between the groups was shown in the occurrence of serious and drug-related adverse events. Three (2%) cases of reversible agranulocytosis occurred in the 193 patients in the safety analysis in the deferiprone group and two (1%) cases of reversible renal and urinary disorders (one case of each) occurred in the 197 patients in the deferasirox group. Compliance was similar between treatment groups: 183 (95%) of 193 patients in the deferiprone group versus 192 (97%) of 197 patients in the deferisirox group. INTERPRETATION In paediatric patients with transfusion-dependent haemoglobinopathies, deferiprone was effective and safe in inducing control of iron overload during 12 months of treatment. Considering the need for availability of more chelation treatments in paediatric populations, deferiprone offers a valuable treatment option for this age group. FUNDING EU Seventh Framework Programme.

中文翻译：

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在患有输血依赖型血红蛋白病（DEEP-2）的小儿患者中评估去铁酮与地拉罗司比较的疗效和安全性：一项多中心，随机，开放标签，非自卑性的3期临床试验。

背景技术依赖于输血的血红蛋白病需要终身使用三种铁螯合剂（去铁酮，地拉西罗或去铁胺）之一进行铁螯合疗法。Deferasirox和Deferiprone是成人输血依赖型血红蛋白病患者使用的仅有的两种口服螯合剂。据我们所知，目前尚无针对小儿患者比较便宜的铁螯合剂去铁酮与地拉罗司进行比较的随机临床试验。我们旨在显示去铁酮与地拉罗司的非劣效性。方法DEEP-2是一项针对患有输血依赖性血红蛋白病的小儿患者（年龄1个月至18岁）的3期，多中心，随机试验。这项研究是在意大利，埃及，希腊，阿尔巴尼亚，塞浦路斯，突尼斯和英国的21家研究医院和大学中进行的。入组时过去两年中，参与者每年至少接受150 mL / kg的红细胞，并接受去铁胺（<100 mg / kg /天）或地拉罗司（<40 mg / kg /天； Deferasirox未注册用于2岁以下的儿童，因此这些患者仅使用deferoxamine）。任何先前的螯合治疗均允许进行7天的清除期。患者被随机分配为1：1接受口服地芬酮（75-100 mg / kg /天）或每日地拉罗司（20-40 mg / kg /天）分散片给药，均调整剂量12个月，分层按年龄（<10岁且≥10岁）分类，并按国家/地区进行平衡。主要功效终点基于血清铁蛋白浓度（所有患者）和心脏MRI T2-star（T2 *；年龄> 10岁的患者）变化的预定义成功标准，以显示每个方案中非铁酮与地拉洛司的非劣效性人群，定义为所有接受研究药物并在基线和治疗1年后均具有可用变量的数据的随机分配患者，且未违反主要方案。非劣效性是基于两组之间成功治疗的患者比例的95％CI差异，并且如果95％CI的下限大于-12·5则显示％。在接受至少一剂研究药物的所有患者中评估安全性。该研究已在EudraCT，2012-000353-31和ClinicalTrials.gov中注册，NCT01825512。结果在2014年3月17日至2016年6月16日之间招募了435名患者，其中393名患者被随机分配至治疗组（去铁酮组194例；地拉罗司组199例）。390例患者中有352例（90％）患有严重的β地中海贫血，27例（7％）患有镰状细胞病，5例（1％）患有thalassodrepanocytosis，其他6例（2％）患有其他血红蛋白病。去铁酮的中位随访时间为379天（IQR 294-392），地拉罗司的中位随访时间为381天（350-392）。建立了非铁酮与地拉洛司的非劣效性（在基线和1年时可获得主要复合疗效终点数据的125例分配了去铁酮的患者中，有69例[55·2％]的治疗成功，而对146例地拉西司的80 [54·8％]的治疗成功，差异0·4％； 95％CI -11·9至12·6）。在严重和药物相关不良事件的发生方面，两组之间没有显着差异。在安全性分析中，去铁酮组中的193例患者中发生了3例（2％）可逆性粒细胞缺乏症，在地拉罗司组中的197例患者中发生了2例（1％）可逆性肾脏和泌尿系统疾病（每例1例） 。各治疗组之间的依从性相似：去铁酮组193例患者中的183名（95％），而去铁酮组197例中192名（97％）。解释对于患有输血依赖型血红蛋白病的小儿患者，去铁酮在治疗12个月内可有效安全地诱导铁超负荷的控制。考虑到有必要在儿科人群中使用更多的螯合疗法，去铁酮为该年龄段的人群提供了宝贵的治疗选择。资助欧盟第七框架计划。