FOP is a disease that causes heterotopic ossification of muscles, tendons and ligaments culminating in severe morbidity and early mortality in affected patients. Like many rare diseases, there are currently no effective treatments available. The STOPFOP trial aims to investigate the effectiveness and safety of the drug AZD0530 for inhibition of HO in patients with FOP. To our knowledge, this is the first publication on the design of a clinical trial in FOP.
Investigating novel drug therapies in FOP poses several unique challenges that we have tried to mitigate in this trial. Firstly, rare diseases by their very definition have a limited number of patients, often distributed across the globe. The low prevalence of FOP, estimated to be 1 in 1 million [
4,
5,
26], and that only a subset of these patients will be both willing to participate and eligible for participation, the STOPFOP project opted for a RCT design combined with open label extension and comparison to a natural history data. This strategy allows for increased statistical power with a lower number of patients. It also allows all participating patients to receive the active study drug, which is a significant motivating factor for participation.
Secondly, FOP patients have a particular sensitivity to certain study procedures [
23]. Exacerbations of FOP, called flare-ups, can be provoked by a range of traumas and inflammatory events [
21]. This includes medical procedures, such as biopsies and intramuscular injections [
27]. To that end, our study procedures are aimed to be as non-invasive as possible. Both established imaging methods such as low-dose whole-body CT (without intravenous contrast), as well as novel imaging methods such as the
18F NaF PET-CT, allow for non-invasive evaluation of efficacy [
6]. All procedures are performed in specialised FOP centers that have medical and paramedical personnel that know how to approach these patients, which minimises risk for patients.
Thirdly, FOP is a slowly progressive disease with significant heterogeneity in clinical progression [
24]. This poses challenges for using hard clinical endpoints such as mortality or progression-free survival. It also poses a risk for heterogeneity in the rate and extent of response to investigative treatments. To mitigate these issues, the study adheres to objective measurements, of disease including the amount of HO on whole-body CT, biological activity of FOP using
18F NaF PET/CT, and the set of core outcomes that have been set by the International Clinical Council on FOP [
23]. In addition, the study is restricted to individuals displaying the classic ALK2 R206H mutation, as other less frequent ALK2 mutations associated with non-classical forms of FOP exhibit substantial variability in natural history and severity [
9,
28]. Due to the limited number of available study subjects, there is always a risk of underpowering in studies on ultra-rare diseases.
Finally, progression of translational research to clinical drug development and hopefully onwards to novel drug therapies for FOP and other (ultra) rare diseases is encumbered by the arduous and expensive nature of drug development combined with a low success rate. Despite legislative efforts to alter the risk-benefit ratio for these drugs, only a small percentage of rare diseases have a form of treatment approved by regulatory authorities [
12]. Thus, drug repositioning – using existing clinical molecules for new disease indications - represents an ideal solution for limiting risks in early clinical studies for rare diseases. This has driven the development of this investigator-initiated trial with a unique cooperation of European and transatlantic dedicated FOP researchers, physicians and patient organizations. In the event of a positive study outcome from the STOPFOP study, AZD0530 may represent a therapy for FOP that can be rapidly progressed due to the availability of extensive safety data from 28 registered clinical trials involving over 600 patients.