Optimism in IBM: a dbRCT Phase III trial of sirolimus in patients with IBM to slow disease progression as measured by the IBM functional rating scale (IBM-FRS)

这项双盲、安慰剂对照的多中心3期研究将探索西罗莫司作为治疗包涵体肌炎(IBM)的新方法的疗效。在IBM中，没有任何药物能够阻止肌肉质量和力量的进行性丧失，这严重降低了生活质量，损害了行走、吞咽和社会参与。这种疾病的病理包括骨骼肌纤维的炎症和变性。据推测，西罗莫司可能通过调节骨骼肌受损的自噬来阻断炎症和退行性变的级联，从而减轻肌肉损伤，促进修复，增强肌肉力量。西罗莫司是一种公认的用于器官移植的免疫抑制剂，最近在IBM的一项安慰剂对照的双盲2期试验中显示了对次要结果的一些有益影响。在目前的研究中，140名患者将在澳大利亚、美国和欧洲的地点进行全球招募。这项研究是由澳大利亚科学基金会授予的一项竞争激烈的拨款推动的。这笔赠款将用于支付澳大利亚站点的费用和电子病例报告等跨国费用。尽管国际学习环境极佳，但不可避免地需要国家资助。缺乏国家资金将对全球试验的可行性构成迫在眉睫的威胁。本提案旨在为德国对全球试验的捐款申请资金。国际试验的干预措施包括口服西罗莫司2毫克，与安慰剂相比，疗程为84周。主要结果衡量指标是疾病进展的减慢，通过从基线到第84周的疾病特定的、有效的功能量表IBM-FRS的平均变化来评估。次要结果测量包括安全性和耐受性，以及其他有临床意义的功能测试，如6分钟步行距离、修改后的计时起跳和肌肉力量。预计包括德国患者在内的这项国际研究将巩固IBM以前对西罗莫司的观察，以确定这种毁灭性疾病的第一种有效治疗方法。

This double-blind, placebo-controlled, multicenter phase-3 study will explore the efficacy of sirolimus as novel approach to treat Inclusion Body Myositis (IBM), a chronic inflammatory myopathy of unknown cause. No drug is capable in IBM to hold the progressive loss of muscle mass and strength, which strongly reduces the quality of life and impairs ambulation, swallowing, and social participation. The disease pathology includes inflammation and degeneration of skeletal muscle fibers. It is hypothesized that sirolimus may intercept the inflammatory and degenerative cascades by modulation of the impaired autophagy in skeletal muscle and, thus, lessen muscle damage, promote repair and enhance muscle strength. Sirolimus is a well-established immunosuppressant for organ transplantation and has recently demonstrated some beneficial effects on secondary outcome measures in a placebo-controlled, double-blind phase 2 trial in IBM. In the present study, 140 patients will be recruited globally at sites in Australia, USA and Europe. The study is facilitated by a highly competitive grant awarded by the Australian Science foundation. The grant will cover expenses for Australian sites and cross-country costs such as electronic case reporting. Despite the excellent international study settings, there is an inevitable need for national funding. Lack of national funding will pose an imminent threat to the feasibility of the global trial. The present proposal aims to request funding for the German contribution to the global trial. Intervention of the international trial consists of 2 mg sirolimus orally for 84 weeks compared to placebo. Primary outcome measure is the slowing of disease progression, assessed by the mean change in the disease specific, validated functional scale IBM-FRS from baseline to week 84. Secondary outcome measures include safety and tolerability and additional clinically meaningful functional tests, such as the 6-minute walking distance, modified timed up-and-go, and muscle strength. It is expected that the international study including the German patients will solidify previous observations on sirolimus in IBM in order to identify the first effective treatment for this devastating disease.