Supplementary materials: Confirmatory long-term efficacy and safety results of ataluren in patients with nmDMD from Study 041, an international, randomized, double-blind, placebo-controlled, phase III trial

These are peer-reviewed supplementary materials for the article 'Confirmatory long-term efficacy and safety results of ataluren in patients with nmDMD from Study 041, an international, randomized, double-blind, placebo-controlled, phase III trial' published in the Journal of Comparative Effectiveness Research.
Supplementary appendixSupplementary figure 1Supplementary figure 2Supplementary figure 3Supplementary figure 4Supplementary figure 5Supplementary table 1: Patients enrolled in Study 041 by countrySupplementary table 2: Study 041 analysis populationsSupplementary table 3: TEAEs reported for ≥ 5% of patients who received ataluren or placebo in the as-treated populationSupplementary table 4: Corticosteroid use and baseline time to stand from supine of < 5 seconds for patients who lost ambulation at week 72 in the ITT populationSupplementary table 5: Time to LoA at week 48 in the ITT population and key subgroupsSupplementary table 6: Time to a 5% persistent worsening and a 30 m decline in 6MWD in the ITT population and the 6MWD 300–400 m subgroupSupplementary table 7: Changes in PUL module scores from baseline to week 72 in the Study 041 ITT population and the 6MWD 300–400 m subgroupAim: To report the efficacy and safety of ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) from the phase III, 72-week, placebo-controlled period of Study 041. Materials & methods: Inclusion criteria: boys with nmDMD aged ≥5 years, on a stable corticosteroid regimen for ≥12 months, and baseline 6-minute walk distance (6MWD) ≥150 m. Randomization: 1:1, ataluren (40 mg/kg/day):placebo. Primary end point: slope of 6MWD change (average rate of change). Secondary end points: changes in 6MWD, time to 10% persistent worsening in 6MWD, North Star Ambulatory Assessment score, timed function tests and safety. Study populations: intention-to-treat; patients aged ≥7 to ≤16 years with baseline 6MWD ≥300 m and stand from supine ≥5 s; patients with baseline 6MWD 300–400 m. Results: In the intention-to-treat population (n = 359), over 72 weeks, ataluren reduced the rate of 6MWD decline by 21% (p = 0.0248), reduced the average 6MWD change (p = 0.0248), delayed time to 10% persistent worsening in 6MWD (p = 0.0078), and reduced North Star Ambulatory Assessment total score decline (p = 0.0235), change in 10 m walk/run time (p = 0.0422) and change in time to climb four stairs (p = 0.0293) versus placebo. In the 6MWD 300–400 m subgroup (n = 169), ataluren reduced the rate of 6MWD decline by 30% (p = 0.0310) versus placebo. Ataluren treatment benefits were seen in secondary end points in this subgroup, except for change in time to descend four stairs. In the 6MWD ≥300 m and time to stand from supine ≥5s subgroup (n = 185), there was a 9% slower rate of 6MWD decline for ataluren versus placebo over 72 weeks (p = 0.3626). Ataluren reduced change in time to climb four stairs (p = 0.0179) versus placebo in this subgroup; no treatment benefits were seen for other secondary end points. Ataluren was well tolerated (serious adverse events: ataluren, 7.1%; placebo, 6.8%); no deaths occurred. Conclusion: Long-term ataluren treatment has a favorable benefit–risk profile, slowing motor function decline in the largest phase III nmDMD study to date.

本材料为发表于《比较疗效研究期刊》（Journal of Comparative Effectiveness Research）的论文《国际多中心随机双盲安慰剂对照Ⅲ期临床试验041中阿塔鲁伦（ataluren）治疗无义突变型杜氏肌营养不良症（nonsense mutation Duchenne muscular dystrophy, nmDMD）患者的确证性长期疗效与安全性结果》的经同行评议补充资料。

补充内容包括：补充附录、补充图1、补充图2、补充图3、补充图4、补充图5；
补充表1：按国家划分的041临床试验入组患者情况
补充表2：041临床试验分析人群
补充表3：按治疗人群统计的、在接受阿塔鲁伦或安慰剂治疗的患者中报告率≥5%的治疗期间出现的不良事件（treatment-emergent adverse events, TEAEs）
补充表4：意向治疗（intention-to-treat, ITT）人群中，第72周丧失行走能力患者的糖皮质激素使用情况及基线仰卧起立时间＜5秒的比例
补充表5：意向治疗人群及关键亚组中第48周的行走丧失时间
补充表6：意向治疗人群及6分钟步行距离（6-minute walk distance, 6MWD）300~400m亚组中，出现5%持续性恶化及6MWD下降30m的时间
补充表7：041临床试验意向治疗人群及6MWD 300~400m亚组中，PUL模块评分从基线至第72周的变化情况

研究目的：报告041Ⅲ期临床试验72周安慰剂对照阶段内，阿塔鲁伦治疗nmDMD患者的疗效与安全性。
材料与方法：
纳入标准：年龄≥5岁的nmDMD男性患儿，接受稳定糖皮质激素治疗≥12个月，基线6MWD≥150m。
随机分组：按1:1比例分配至阿塔鲁伦组（40mg/kg/日）与安慰剂组。
主要终点：6MWD变化斜率（平均变化速率）。
次要终点：6MWD变化值、6MWD出现10%持续性恶化的时间、北星行走评估量表（North Star Ambulatory Assessment）评分、计时功能测试结果及安全性。
研究人群：意向治疗人群；年龄≥7岁且≤16岁、基线6MWD≥300m且仰卧起立时间≥5秒的患者；基线6MWD为300~400m的患者。

研究结果：在意向治疗人群（n=359）中，72周随访期内，与安慰剂组相比，阿塔鲁伦组的6MWD下降速率降低21%（p=0.0248），平均6MWD变化量得到改善（p=0.0248），延迟了6MWD出现10%持续性恶化的时间（p=0.0078），并减缓了北星行走评估量表总分下降（p=0.0235）、10米行走/跑步时间变化（p=0.0422）以及爬四层楼梯时间变化（p=0.0293）。
在6MWD 300~400m亚组（n=169）中，与安慰剂组相比，阿塔鲁伦组的6MWD下降速率降低30%（p=0.0310），该亚组的次要终点均展现出阿塔鲁伦的治疗获益，仅下四层楼梯时间变化除外。
在6MWD≥300m且仰卧起立时间≥5秒的亚组（n=185）中，72周随访期内，阿塔鲁伦组的6MWD下降速率较安慰剂组慢9%（p=0.3626）；该亚组中，阿塔鲁伦可改善爬四层楼梯时间变化（p=0.0179），其余次要终点未观察到治疗获益。
阿塔鲁伦耐受性良好（严重不良事件发生率：阿塔鲁伦组7.1%，安慰剂组6.8%），未发生死亡病例。

研究结论：长期阿塔鲁伦治疗具有良好的获益-风险比，在目前已开展的最大规模nmDMDⅢ期临床试验中，可延缓运动功能衰退。