Nagy Sara, Hafner Patricia, Schmidt Simone, Rubino-Nacht Daniela, Schädelin Sabine, Bieri Oliver, Fischer Dirk
Division of Developmental- and Neuropaediatrics, University Children's Hospital Basel (UKBB), University of Basel, Spitalstrasse 33, Postfach, 4031, Basel, Switzerland.
Department of Neurology, University Hospital Basel, University of Basel, Petersgraben 4, 4031, Basel, Switzerland.
Trials. 2019 Nov 21;20(1):637. doi: 10.1186/s13063-019-3740-6.
Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disorder of childhood with a devastating disease course. Several targeted gene therapies and molecular approaches have been or are currently being tested in clinical trials; however, a causative therapy is still not available and best supportive care is limited to oral glucocorticoids with numerous long-term side effects. Tamoxifen is a selective estrogen receptor regulator, and shows antioxidant actions and regulatory roles in the calcium homeostasis besides its antitumor activity. In a mouse model of DMD, oral tamoxifen significantly improved muscle strength and reduced muscle fatigue. This multicenter, randomized, double-blind, placebo-controlled phase III trial aims to demonstrate safety and efficacy of tamoxifen over placebo in pediatric patients with DMD. After completion of the double-blind phase, an open-label extension of the study will be offered to all participants.
METHODS/DESIGN: At least 71 ambulant and up to 20 nonambulant patients with DMD are planned to be enrolled at multiple European sites. Patients will be randomly assigned to receive either tamoxifen 20 mg or placebo daily over 48 weeks. In the open-label extension phase, all patients will be offered tamoxifen for a further 48 weeks. The primary endpoint of the double-blind phase is defined as the change of the D1 domain of the motor function measure in ambulant patients or a change of the D2 domain in nonambulant patients under tamoxifen compared to placebo. Secondary outcome measures include change in timed function tests, quantitative muscle testing, and quantitative magnetic resonance imaging of thigh muscles. Laboratory analyses including biomarkers of tamoxifen metabolism and muscle dystrophy will also be assessed.
The aim of the study is to investigate whether tamoxifen can reduce disease progression in ambulant and nonambulant patients with DMD over 48 weeks. Motor function measures comprise the primary endpoint, whereas further clinical and radiological assessments and laboratory biomarkers are performed to provide more data on safety and efficacy. An adjacent open-label extension phase is planned to test if earlier initiation of the treatment with tamoxifen (verum arm of double-blind phase) compared to a delayed start can reduce disease progression more efficiently.
ClinicalTrials.gov, NCT03354039. Registered on 27 November 2017.
杜氏肌营养不良症（DMD）是一种儿童期遗传性神经肌肉疾病，疾病进程具有毁灭性。几种靶向基因疗法和分子方法已经或正在进行临床试验；然而，仍没有病因性治疗方法，最佳支持性治疗仅限于口服糖皮质激素，且有许多长期副作用。他莫昔芬是一种选择性雌激素受体调节剂，除了具有抗肿瘤活性外，还具有抗氧化作用以及在钙稳态中的调节作用。在DMD小鼠模型中，口服他莫昔芬可显著改善肌肉力量并减轻肌肉疲劳。这项多中心、随机、双盲、安慰剂对照的III期试验旨在证明他莫昔芬对比安慰剂在DMD儿科患者中的安全性和有效性。双盲阶段完成后，将向所有参与者提供该研究的开放标签扩展阶段。
方法/设计：计划在多个欧洲地点招募至少71名能行走的和最多20名不能行走的DMD患者。患者将被随机分配，在48周内每天接受20毫克他莫昔芬或安慰剂治疗。在开放标签扩展阶段，所有患者将再接受48周的他莫昔芬治疗。双盲阶段的主要终点定义为与安慰剂相比，能行走患者在接受他莫昔芬治疗后运动功能测量D1域的变化或不能行走患者D2域的变化。次要结局指标包括定时功能测试、定量肌肉测试以及大腿肌肉定量磁共振成像的变化。还将评估包括他莫昔芬代谢和肌肉营养不良生物标志物在内的实验室分析。
该研究的目的是调查他莫昔芬在48周内是否能减缓能行走和不能行走的DMD患者的疾病进展。运动功能测量构成主要终点，而进行进一步的临床和放射学评估以及实验室生物标志物检测以提供更多关于安全性和有效性的数据。计划进行一个相邻的开放标签扩展阶段，以测试与延迟开始相比，更早开始使用他莫昔芬治疗（双盲阶段的试验组）是否能更有效地减缓疾病进展。
ClinicalTrials.gov，NCT03354039。于2017年11月27日注册。
