Abstract
Background. Inclusion body myositis (IBM) is a progressive disabling muscle condition without any effective disease-modifying therapies. Sirolimus works by blocking the activity of effector T cells whilst preserving T regulatory cells, as well as inducing autophagy, thereby having effects on both the chronic inflammation and abnormal proteostasis that contribute to myocyte death in IBM. Sirolimus was recently trialled in 44 French IBM patients in a proof-of-concept monocentric controlled phase 2 study. While the primary outcome was not met, a number of secondary outcome measures suggested a positive impact on disease progression.
Methods. Optimism in IBM (NCT04789070; ANZCTR: ACTRN- 12620001226998p) is a double-blind randomised controlled phase 3 trial investigating the potential effect of Sirolimus on stabilising or slowing disease progression in patients with IBM as measured by the IBM Functional Rating Scale (IBM-FRS). In this investigator-initiated trial, we will be comparing 2 mg Sirolimus vs Placebo, in a minimum of 140 participants across 14 trial sites in Australia, Europe, and the United States of America over 84 weeks. The primary outcome measure is the comparison between Sirolimus and placebo on the mean change in patient function from Baseline to Week 84 as assessed by the IBM-FRS. Secondary outcomes include changes from Baseline to Week 84 in the 6- and 2- minute walk test, modified Timed-up-and-go, a number of patient reported outcomes, manual and quantitative muscle tests, and measures to assess sirolimus safety and tolerability.
Results. This study is about to commence, but the prolonged set-up phase high¬lights the challenges in establishing a multi-centre trial across the world. In addition to securing funding, collaboration and coordination are both absolutely necessary in rare disease research. These require hard work, tenacity and dedication from clinicians, project managers and study co-ordinators, strong commitment of patients to be engaged at different stages and vigorous support from patient advocacy groups across the world. Moreover, awareness of IBM natural history, data-driven selection of robust outcome tools and appropriate design of patient inclusion and exclusion criteria are critically important to optimise the probability to detect a positive signal. Some of the key challenges include obtaining sufficient funding to fund placebo and pharmacy costs, to support site costs and for central data co-ordination and monitoring, in addition to the complex web of contracts that must be negotiated and agreed in different regulatory environments across the world. All these important challenges are surmountable but time-consuming.
Conclusions. Having a network of similarly-minded and driven clinicians with appropriate support staff across the world who care for cohorts of well phenotyped patients is a solid foundation for global clinical trials. Whilst in an ideal world, these centres would simply follow the same protocol and combine results, the reality of the costs and time involved in running clinical trials and the governance required to ensure these are carried out in a standardised manner across the world, means that significant challenges and prolonged starting timelines remain even in established clinical trial networks. We believe we have established rigorous processes that enhance team collaboration and coordination that are essential for the successful initiation and completion of our study – Optimism in IBM.