Abstract：
BACKGROUND: 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.
METHODS: 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 ClinicalTrials.gov, NCT02851797, and is complete.
RESULTS: 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 vs 11 [18%] of 61 receiving placebo) and vomiting (34 [29%] vs 8 [13%]); no treatment-related deaths occurred.
CONCLUSIONS: 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.
BACKGROUND: Italfarmaco.
METHODS: 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 ClinicalTrials.gov, NCT02851797, and is complete.
RESULTS: 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 vs 11 [18%] of 61 receiving placebo) and vomiting (34 [29%] vs 8 [13%]); no treatment-related deaths occurred.
CONCLUSIONS: 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.
BACKGROUND: Italfarmaco.
摘要：
背景：杜氏肌营养不良症，最常见的儿童肌肉萎缩症，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，组蛋白脱乙酰酶抑制剂，可能有助于抵消这种缺陷的影响。我们旨在评估givinostat治疗Duchenne肌营养不良的安全性和有效性。
方法：这个多中心，随机化，双盲,安慰剂对照,在11个国家的41个三级医疗中心进行了3期试验.符合条件的参与者是救护车，男性,年龄至少6岁，经基因证实诊断为杜氏肌营养不良症，完成两次四楼爬升评估，平均值为8s或更小(≤1s方差)，上升时间至少为3秒，但不到10秒，并已接受全身性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进行分配），每天两次接受口服givinostat或匹配的安慰剂，持续72周，通过合并使用类固醇进行分层。孩子们,调查员,和现场和赞助商的工作人员被蒙住了治疗分配。剂量是灵活的，基于体重，如果不能容忍，就会减少。男孩根据其基线股外侧脂肪含量（VLFF；通过磁共振波谱测量）分为两组：A组包括VLFF超过5％但不超过30％的男孩，而B组包括VLFF为5%或更低的男孩，或超过30%。主要终点比较了givinostat和安慰剂对基线和72周之间四楼爬升评估结果变化的影响，在意向治疗中，A组人口。在接受至少一个剂量的研究药物的所有随机分配的男孩中评估安全性。当A组的前50名男孩完成12个月的治疗时，进行了临时徒劳评估，之后,使用来自四楼爬升评估的掩蔽数据调整样本量.此外，方案修订后,吉维诺他的起始剂量减少.该试验已在ClinicalTrials.gov注册，NCT02851797，完成。
结果：在2017年6月6日至2022年2月22日之间，对359名男孩进行了资格评估。其中,179人被纳入研究(中位年龄9·8岁[IQR8·1-11·0])，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%)男孩完成了研究.在登记的179名男孩中，A组120例(67%)(81例givinostat和39例安慰剂)；其中，114(95%)完成了研讨。对于A组的参与者，比较72周时四楼爬升评估的结果和基线，接受givinostat的男孩的几何最小二乘平均比率为1·27(95%CI1·17-1·37),接受安慰剂的男孩的几何最小二乘平均比率为1·48(1·32-1·66)(比率0·86,95%CI0·745-0·989;p=0·035).givinostat组最常见的不良事件是腹泻（118名男孩中的43[36％]对接受安慰剂的61名男孩中的11[18％]）和呕吐（34[29％]对8[13％]）；没有治疗相关的死亡发生。
结论：在患有Duchenne肌营养不良症的男孩中，在研究期间，两组的四楼爬升评估结果均恶化；然而，givinostat组的下降幅度明显小于安慰剂组.经过中期安全性分析后，吉维诺他的剂量减少了，但没有新的安全信号报告。正在进行的扩展研究正在评估givinostat在Duchenne肌营养不良患者中的长期安全性和有效性。
背景：Italfarmaco。
方法：这个多中心，随机化，双盲,安慰剂对照,在11个国家的41个三级医疗中心进行了3期试验.符合条件的参与者是救护车，男性,年龄至少6岁，经基因证实诊断为杜氏肌营养不良症，完成两次四楼爬升评估，平均值为8s或更小(≤1s方差)，上升时间至少为3秒，但不到10秒，并已接受全身性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进行分配），每天两次接受口服givinostat或匹配的安慰剂，持续72周，通过合并使用类固醇进行分层。孩子们,调查员,和现场和赞助商的工作人员被蒙住了治疗分配。剂量是灵活的，基于体重，如果不能容忍，就会减少。男孩根据其基线股外侧脂肪含量（VLFF；通过磁共振波谱测量）分为两组：A组包括VLFF超过5％但不超过30％的男孩，而B组包括VLFF为5%或更低的男孩，或超过30%。主要终点比较了givinostat和安慰剂对基线和72周之间四楼爬升评估结果变化的影响，在意向治疗中，A组人口。在接受至少一个剂量的研究药物的所有随机分配的男孩中评估安全性。当A组的前50名男孩完成12个月的治疗时，进行了临时徒劳评估，之后,使用来自四楼爬升评估的掩蔽数据调整样本量.此外，方案修订后,吉维诺他的起始剂量减少.该试验已在ClinicalTrials.gov注册，NCT02851797，完成。
结果：在2017年6月6日至2022年2月22日之间，对359名男孩进行了资格评估。其中,179人被纳入研究(中位年龄9·8岁[IQR8·1-11·0])，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%)男孩完成了研究.在登记的179名男孩中，A组120例(67%)(81例givinostat和39例安慰剂)；其中，114(95%)完成了研讨。对于A组的参与者，比较72周时四楼爬升评估的结果和基线，接受givinostat的男孩的几何最小二乘平均比率为1·27(95%CI1·17-1·37),接受安慰剂的男孩的几何最小二乘平均比率为1·48(1·32-1·66)(比率0·86,95%CI0·745-0·989;p=0·035).givinostat组最常见的不良事件是腹泻（118名男孩中的43[36％]对接受安慰剂的61名男孩中的11[18％]）和呕吐（34[29％]对8[13％]）；没有治疗相关的死亡发生。
结论：在患有Duchenne肌营养不良症的男孩中，在研究期间，两组的四楼爬升评估结果均恶化；然而，givinostat组的下降幅度明显小于安慰剂组.经过中期安全性分析后，吉维诺他的剂量减少了，但没有新的安全信号报告。正在进行的扩展研究正在评估givinostat在Duchenne肌营养不良患者中的长期安全性和有效性。
背景：Italfarmaco。
