Duchenne muscular dystrophy, the most common childhood muscular dystrophy, is caused by dystrophin deficiency. Preclinical and phase 2 study data have suggested that givinostat, a histone deacetylase inhibitor, might help to counteract the effects of this deficiency. We aimed to evaluate the safety and efficacy of givinostat in the treatment of Duchenne muscular dystrophy. This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 41 tertiary care sites in 11 countries. Eligible participants were ambulant, male, and aged at least 6 years, had a genetically confirmed diagnosis of Duchenne muscular dystrophy, completed two four-stair climb assessments with a mean of 8 s or less (≤1 s variance), had a time-to-rise of at least 3 s but less than 10 s, and had received systemic corticosteroids for at least 6 months. Participating boys were randomly assigned (2:1, allocated according to a list generated by the interactive response technology provider) to receive either oral givinostat or matching placebo twice a day for 72 weeks, stratified by concomitant steroid use. Boys, investigators, and site and sponsor staff were masked to treatment assignment. The dose was flexible, based on weight, and was reduced if not tolerated. Boys were divided into two groups on the basis of their baseline vastus lateralis fat fraction (VLFF; measured by magnetic resonance spectroscopy): group A comprised boys with a VLFF of more than 5% but no more than 30%, whereas group B comprised boys with a VLFF of 5% or less, or more than 30%. The primary endpoint compared the effects of givinostat and placebo on the change in results of the four-stair climb assessment between baseline and 72 weeks, in the intention-to-treat, group A population. Safety was assessed in all randomly assigned boys who received at least one dose of study drug. When the first 50 boys in group A completed 12 months of treatment, an interim futility assessment was conducted, after which the sample size was adapted using masked data from the four-stair climb assessments. Furthermore, the starting dose of givinostat was reduced following a protocol amendment. This trial is registered with , , and is complete. Between June 6, 2017, and Feb 22, 2022, 359 boys were assessed for eligibility. Of these, 179 were enrolled into the study (median age 9·8 years [IQR 8·1–11·0]), all of whom were randomly assigned (118 to receive givinostat and 61 to receive placebo); 170 (95%) boys completed the study. Of the 179 boys enrolled, 120 (67%) were in group A (81 givinostat and 39 placebo); of these, 114 (95%) completed the study. For participants in group A, comparing the results of the four-stair climb assessment at 72 weeks and baseline, the geometric least squares mean ratio was 1·27 (95% CI 1·17–1·37) for boys receiving givinostat and 1·48 (1·32–1·66) for those receiving placebo (ratio 0·86, 95% CI 0·745–0·989; p=0·035). The most common adverse events in the givinostat group were diarrhoea (43 [36%] of 118 boys 11 [18%] of 61 receiving placebo) and vomiting (34 [29%] 8 [13%]); no treatment-related deaths occurred. Among ambulant boys with Duchenne muscular dystrophy, results of the four-stair climb assessment worsened in both groups over the study period; however, the decline was significantly smaller with givinostat than with placebo. The dose of givinostat was reduced after an interim safety analysis, but no new safety signals were reported. An ongoing extension study is evaluating the long-term safety and efficacy of givinostat in patients with Duchenne muscular dystrophy. Italfarmaco.

中文翻译：

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givinostat 对杜氏肌营养不良症 (EPIDYS) 男孩的安全性和有效性：一项多中心、随机、双盲、安慰剂对照 3 期试验

杜氏肌营养不良症是最常见的儿童肌营养不良症，是由肌营养不良蛋白缺乏引起的。临床前和 2 期研究数据表明，givinostat（一种组蛋白脱乙酰酶抑制剂）可能有助于抵消这种缺陷的影响。我们的目的是评估 givinostat 治疗杜氏肌营养不良症的安全性和有效性。这项多中心、随机、双盲、安慰剂对照的 3 期试验在 11 个国家的 41 个三级医疗机构进行。符合资格的参与者是能活动的男性，年龄至少 6 岁，具有杜氏肌营养不良症的基因诊断，完成了两次四楼梯攀爬评估，平均时间为 8 秒或更少（≤ 1 秒方差），具有时间-上升时间至少 3 秒但少于 10 秒，并且已接受全身皮质类固醇治疗至少 6 个月。参与的男孩被随机分配（2:1，根据交互式反应技术提供商生成的列表分配）接受口服 givinostat 或匹配的安慰剂，每天两次，持续 72 周，并根据同时使用类固醇进行分层。男孩、研究人员、现场和赞助商工作人员都对治疗分配情况不知情。剂量根据体重灵活调整，如果不能耐受则减少剂量。根据基线股外侧肌脂肪分数（VLFF；通过磁共振波谱测量）将男孩分为两组：A 组包括 VLFF 超过 5% 但不超过 30% 的男孩，B 组包括 VLFF 的男孩VLFF 为 5% 或更低，或超过 30%。主要终点比较了意向治疗 A 组人群中 givinostat 和安慰剂对基线和 72 周之间四楼梯攀登评估结果变化的影响。对所有接受至少一剂研究药物的随机分配的男孩进行安全性评估。当 A 组中的前 50 名男孩完成 12 个月的治疗后，进行了临时无效评估，之后使用四级爬楼梯评估的屏蔽数据调整了样本量。此外，在方案修订后，givinostat 的起始剂量有所减少。该试用已在 、 、 注册，并已完成。 2017年6月6日至2022年2月22日期间，共有359名男孩接受了资格评估。其中，179 人被纳入研究（中位年龄 9·8 岁 [IQR 8·1–11·0]），所有这些人都被随机分配（118 人接受 givinostat，61 人接受安慰剂）； 170 名 (95%) 男孩完成了这项研究。在入组的 179 名男孩中，120 名 (67%) 属于 A 组（81 名吉维诺他和 39 名安慰剂）；其中 114 人 (95%) 完成了研究。对于 A 组参与者，比较 72 周时四级爬楼梯评估结果和基线，接受 givinostat 和 1 组男孩的几何最小二乘平均比为 1·27 (95% CI 1·17–1·37)。接受安慰剂的患者为·48 (1·32–1·66)（比率 0·86，95% CI 0·745–0·989；p=0·035）。givinostat 组最常见的不良事件是腹泻（118 名男孩中有 43 名 [36%]，接受安慰剂的 61 名男孩中有 11 名 [18%]）和呕吐（34 名 [29%] 8 名 [13%]）。没有发生与治疗相关的死亡。在患有杜氏肌营养不良症的步行男孩中，在研究期间，两组的四楼梯攀登评估结果均恶化；然而，givinostat 组的下降幅度明显小于安慰剂组。中期安全性分析后，吉维诺他的剂量减少，但没有报告新的安全信号。一项正在进行的扩展研究正在评估 givinostat 对杜氏肌营养不良症患者的长期安全性和有效性。意大利法马科。