Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial
Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial
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DOI：
10.1016/s1474-4422(10)70182-4
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发表时间：
2010-09-01
期刊：
影响因子：
48
通讯作者：
Sobue, Gen
中科院分区：
文献类型：
--
作者：
Katsuno, Masahisa;Banno, Haruhiko;Sobue, Gen
研究背景脊髓延髓肌萎缩症是一种遗传性运动神经元疾病，由雄激素受体中的多聚谷氨酰胺束扩张引起。尽管亮丙瑞林在一项II期试验中抑制了致病性雄激素受体的蓄积，但目前尚无脊髓和延髓肌萎缩症的治疗方法。我们的目的是评估亮丙瑞林的疗效和安全性脊髓和延髓muscularatrophy.Methods日本SBMA干预试验TAP-144-SR（JASMITT）是一个48周，随机，双盲，安慰剂对照试验，在14家医院之间，2006年8月，2008年3月。脊髓性和延髓性肌萎缩患者按最小化随机分配（1：1）至皮下注射11. 25 mg亮丙瑞林或相同的安慰剂组，每12周一次。患者和研究者均对治疗分配设盲。主要终点是咽钡残留，这表明在第48周通过视频荧光造影测量的不完全的团注清除。所有被随机分配并至少接受过一次视频X线透视评估的患者均被纳入分析。本研究在JMACCT临床试验注册处注册，编号为JMA-IIA 00009，在UMIN临床试验注册处注册，编号为UMIN 00000465。结果204例患者被随机分配，199例开始治疗：100例接受亮丙瑞林治疗，99例接受安慰剂治疗。第48周时，亮丙瑞林组初始吞咽后的咽钡残留变化为-5.1%（SD 21.0），安慰剂组为0.2%（18.2）（组间差异为-5.3%; 95% CI为-10.8至0.3; p=0.063）。第48周时，逐片吞咽后咽钡残留的平均差异为-3.2%（-6.4至0.0; p=0.049），但对基线数据进行协变量校正后，两组间无显著差异（-4.1至1.6; p=0.392）。在一项预先确定的亚组分析中，在病程小于10年的患者中，亮丙瑞林治疗与初始吞咽后钡残留减少的相关性大于安慰剂（组间差异为-9.8、-17.1至-2.5; p=0.009）。两组之间药物相关不良事件的数量无显著差异（亮丙瑞林组57/100例，安慰剂组54/99例; p=0.727）。解释亮丙瑞林治疗48周未显示对脊髓和延髓肌萎缩症患者的吞咽功能有显著影响，尽管耐受性良好。疾病持续时间可能影响亮丙瑞林的疗效，因此应在患者亚群中进行具有敏感结局指标的进一步临床试验。
Background Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor. At present there are no treatments for spinal and bulbar muscular atrophy, although leuprorelin suppressed the accumulation of pathogenic androgen receptors in a phase 2 trial. We aimed to assess the efficacy and safety of leuprorelin for spinal and bulbar muscular atrophy.Methods The Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) was a 48-week, randomised, double-blind, placebo-controlled trial done at 14 hospitals between August, 2006, and March, 2008. Patients with spinal and bulbar muscular atrophy were randomly assigned (1:1) by minimisation to subcutaneous 11.25 mg leuprorelin or identical placebo every 12 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was pharyngeal barium residue, which indicates incomplete bolus clearance, measured at week 48 by videofluorography. All patients who were randomly assigned and who were assessed with videofluorography at least once were included in the analyses. This study is registered with the JMACCT clinical trials registry, number JMA-IIA00009, and the UMIN clinical trials registry, number UMIN000000465.Findings 204 patients were randomly assigned and 199 started treatment: 100 with leuprorelin and 99 with placebo. At week 48, the pharyngeal barium residue after initial swallowing had changed by -5.1% (SD 21.0) in the leuprorelin group and by 0.2% (18.2) in the placebo group (difference between groups -5.3%; 95% CI -10.8 to 0.3; p=0.063). The mean difference in pharyngeal barium residue after piecemeal deglutition at week 48 was -3.2% (-6.4 to 0.0; p=0.049), but there was no significant difference between the groups after covariate adjustment for the baseline data (-4.1 to 1.6; p=0.392). In a predefined subgroup analysis, leuprorelin treatment was associated with a greater reduction in barium residue after initial swallowing than was placebo in patients with a disease duration less than 10 years (difference between groups -9.8, -17.1 to -2.5; p=0.009). There were no significant differences in the number of drug-related adverse events between groups (57 of 100 in the leuprorelin group and 54 of 99 in the placebo group; p=0.727).Interpretation 48 weeks of treatment with leuprorelin did not show significant effects on swallowing function in patients with spinal and bulbar muscular atrophy, although it was well tolerated. Disease duration might influence the efficacy of leuprorelin and thus further clinical trials with sensitive outcome measures should be done in subpopulations of patients.