Background Lymphatic anomalies (LAs) include several disorders in which abnormal lymphatic tissue invades the neck, chest, and various organs. Progressive cases may result in lethal outcomes and have proven difficult to treat. Sirolimus is showing promising results in the management of vascular anomalies. We examined the efficacy and safety of sirolimus treatment in patients with progressive LAs. Methods All patients with LAs treated with sirolimus from May 2015 to September 2018 were included. They received oral sirolimus once a day and the dose was adjusted so that the trough concentration remained within 5–15 ng/mL. We prospectively reviewed the response to drugs (the response rate of radiological volumetric change of the target lesion), severity scores, reported quality of life (QOL), and adverse effects at 6 months after administration. Results Twenty patients (five with cystic lymphatic malformation (LM), three with kaposiform lymphangiomatosis, three with generalized lymphatic anomaly, six with Gorham-Stout disease, and three with central conducting lymphatic anomaly) were treated with sirolimus at our institution. Fifty percent of patients (10/20) demonstrated a partial response by a radiological examination and a significant improvement in disease severity and QOL scores ( P = 0.0020 and P = 0.0117, respectively). Ten patients who had no reduction in lesion size (stable disease group) showed no significant improvement in disease severity and QOL scores. Eighty percent of patients (16/20) had side effects, such as stomatitis, infection, and hyperlipidemia. Conclusions Sirolimus impacts the reduction of the lymphatic tissue volume of LMs and could lead to improvement in clinical symptoms and QOL. Trial registration UMIN Clinical Trials Registry, UMIN000016580 . Registered 19 February 2015, Electronic supplementary material The online version of this article (10.1186/s13023-019-1118-1) contains supplementary material, which is available to authorized users.
What is known and objective: There are no clinical reports that have compared topiroxostat, a selective xanthine oxidase inhibitor, with allopurinol in serum urate-lowering efficacy. The aim of this study was to compare the efficacy and safety of topiroxostat and allopurinol in Japanese hyperuricemic patients with or without gout. Methods: A phase 3, multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group study conducted in Japan. Patients who had inadequate serum urate levels (a gout patient: serum urate level ≥416Á4 lmol/L; an asymptomatic hyperuricemic patient with specific complications (urinary lithi-asis, hypertension, hyperlipidemia and/or diabetes): serum urate level ≥475Á8 lmol/L; and an asymptomatic hyperuricemic patient with no specific complications: serum urate level ≥535Á3 lmol/L) were randomized to topiroxostat 120 mg/day or allopurinol 200 mg/day, with an equal allocation ratio, for 16 weeks. To prevent the onset of gouty arthritis by rapid serum urate reduction, these doses were increased in a stepwise manner. The primary efficacy endpoint was the per cent change in serum urate level from baseline to the final visit. Results and discussion: Overall, 206 patients were randomly assigned to topiroxostat and allopurinol. Two hundred and three patients (allopurinol: n = 105, topiroxostat: n = 98) received at least one dose of the study drug and had their serum urate level assessed at least once. The baseline characteristics were comparable between groups. The mean age of patients was 53Á0 AE 11Á4 years and 99% of patients were male. The primary efficacy endpoint was À34Á3 AE 11Á1% in the allopurinol group (n = 105) and À36Á3 AE 12Á7% in the topiroxostat group (n = 98). Non-inferiority of the serum urate-lowering efficacy of topirox-ostat to allopurinol was proved by the predefined non-inferiority margin (95% confidence interval, À5Á3 to 1Á3%). The overall incidences of adverse events and adverse drug reactions were similar between both groups. What is new and conclusion: Topiroxostat 120 mg/day provides non-inferior serum urate reduction compared with allopurinol 200 mg/day and is well tolerated in Japanese hyperuricemic patients with or without gout. WHAT IS KNOWN AND OBJECTIVE Gout is a common disease in adult males, and its acute symptom, the so-called gout attack, causes impaired quality of life. 1 Because gout is related to monosodium urate crystal deposition, a causative disease of gout is hyperuricemia, which is defined as a serum urate level >416Á4 lmol/L in Japan. 2 Therefore, it is essential to control hype-ruricemia in order to treat gout and its related disorders such as gouty arthritis. Surprisingly, the prevalence of hyperuricemia in male was approximately 20% in United States and 15-20% in Japan. 3,4 Recent clinical reports have suggested a link between high serum urate levels and life-threatening diseases such as cardio-vascular disease, chronic kidney disease (CKD) and hyperten-sion. 5-10 Therefore, the management of hyperuricemia has become increasingl...
IntroductionLymphatic 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.MethodsThis 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.ResultsThis 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.ConclusionsWe 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.
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