Efficacy and safety of sirolimus treatment for intractable lymphatic anomalies: A study protocol for an open-label,...

Lymphatic anomalies (LAs) refer to a group of diseases involving systemic dysplasia of lymphatic vessels. These lesions are classified as cystic lymphatic malformation (macrocystic, microcystic or mixed), generalized lymphatic anomaly, and Gorham-Stout disease. LAs occur mainly in childhood, and present with various symptoms including chronic airway problems, recurrent infection, and organ disorders. Individuals with LAs often experience progressively worsening symptoms with a deteriorating quality of life. Although limited treatment options are available, their efficacy has not been validated in prospective clinical trials, and are usually based on case reports. Thus, there are no validated standards of care for these patients because of the lack of prospective clinical trials.

This open-label, single-arm, multicenter, prospective study will assess the efficacy and safety of a mammalian target of the rapamycin inhibitor sirolimus in the treatment of intractable LAs. Participants will receive oral sirolimus once a day for 52 weeks. The dose is adjusted so that the nadir concentration remains within 5-15 ng/ml. The primary endpoint is the response rate of radiological volumetric change of the target lesion confirmed by central review at 52 weeks after treatment. The secondary endpoints are the response rates at 12 and 24 weeks, respiratory function, pleural effusion, ascites, blood coagulation parameters, bleeding, pain, quality of life, activities of daily living, adverse events, side effects, laboratory examinations, vital signs, and pharmacokinetic data.

This is among the first multicenter studies to evaluate sirolimus treatment for intractable LAs, and few studies to date have focused on the standard assessment of the efficacy for LAs treatment. Our protocol uses novel, uncomplicated methods for radiological assessment, with reference to the results of our previous retrospective survey and historical control data from the literature.

We propose a multicenter study to investigate the efficacy and safety of sirolimus for intractable LAs (SILA study; trial registration UMIN000028905). Our results will provide pivotal data to support the approval of sirolimus for the treatment of intractable LAs.