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A multicenter, single-arm, prospective study assessing efficacy and safety of the Sirolimus in the Treatment of intractable vascular anomalies (Sirolimus for intractable vascular anomalies)

A multicenter, single-arm, prospective study assessing efficacy and safety of the Sirolimus in the Treatment of intractable vascular anomalies (Sirolimus for intractable vascular anomalies)

131

A total of 131 patients were enrolled in this study, and all 131 eligible patients received the investigational drug. Among them, eight patients were enrolled more than once after a certain period and were treated as the same cases. As a result, the safety analysis population consisted of 123 patients. Of these 123 patients, 53 discontinued the study, while 70 completed treatment with the investigational drug. Additionally, since eight patients were carried over from a preceding clinical trial, the efficacy analysis population was defined as 115 patients, excluding those continued cases.

Patient enrollment proceeded smoothly from the start of the study and was completed in December 2022. During the study period, the planned number of participants was 130; however, informed consent was obtained from 131 patients, and all 131 patients received the investigational drug. Of these, 74 patients completed the study and 57 discontinued. No cases required compensation. The final administration of the investigational drug took place in October 2024.

Among the 123 patients included in the safety analysis population, adverse events occurred in 48 patients (39.0%), and adverse drug reactions were observed in 44 patients (35.8%). Adverse events and adverse drug reactions that occurred in two or more patients included stomatitis, acneiform dermatitis, cellulitis, fever, neutropenia, upper respiratory tract infection, soft tissue infection, diarrhea, gastroenteritis, pneumonia, sepsis, and hypertriglyceridemia. Serious adverse events (including deaths) occurred in 19 of the 123 patients (15.4%) in the safety analysis population, of which 14 patients (11.4%) experienced serious adverse drug reactions. Adverse events leading to death were sepsis (2 patients; 2 cases), and one case each of respiratory failure, gastroenteritis, and heart failure (the gastroenteritis and sepsis occurred in the same patient). Among these, the causal relationship with the investigational drug could not be ruled out for the two cases of sepsis and the case of gastroenteritis.

Among the 123 patients included in the safety analysis population, adverse events occurred in 48 patients (39.0%), and adverse drug reactions were observed in 44 patients (35.8%). Adverse events and adverse drug reactions that occurred in two or more patients included stomatitis, acneiform dermatitis, cellulitis, fever, neutropenia, upper respiratory tract infection, soft tissue infection, diarrhea, gastroenteritis, pneumonia, sepsis, and hypertriglyceridemia. Although the study population consisted of patients with severe disabilities or life-threatening conditions, serious adverse events, including deaths, occurred in 19 of the 123 patients (15.4%). Following sirolimus administration, reduction in target lesion size was observed in more than half of the patients in the efficacy analysis population and in more than one-third of those with lymphatic disorders at both 24 and 52 weeks after treatment initiation. At week 52, improvements from baseline were also observed in anemia, blood coagulation parameters, bleeding tendency, pain (VAS), activities of daily living (Karnofsky Performance Status and Lansky Play-Performance Status), and quality of life (PedsQL). These findings indicate that sirolimus demonstrates promising efficacy for refractory vascular and lymphatic disorders in terms of response rate, disease control, and patient quality of life.

These results demonstrated the safety and efficacy of sirolimus for refractory vascular and lymphatic disorders, confirming that sirolimus is a valuable therapeutic option for these conditions. However, when administering sirolimus to patients with refractory vascular and lymphatic disorders, it is essential to ensure that the therapeutic benefits outweigh the potential risks, and the drug should be administered with careful monitoring of the patient's condition.

Mar. 31, 2026

No

Individual participant data will not be shared.

https://jrct.mhlw.go.jp/latest-detail/jRCTs031180290

Ozeki Michio

Gifu University Hospital

1-1 Yanagido, Gifu City, Gifu

michioo@gifu-u.ac.jp

Ozeki Michio

Gifu University Hospital

1-1 Yanagido, Gifu City, Gifu

+81-58-230-6386

michioo@gifu-u.ac.jp

Complete

Mar. 15, 2019

Interventional

single arm study

open(masking not used)

no treatment control/standard of care control

single assignment

treatment purpose

1) Patients with intractable vascular anomaly diagnosed by the investigator/subinvestigator
2) Patients must have vascular anomalies that have severe complication or intractable symptoms.#
3) Normal liver, renal, and cardiac function at entry
Total bilirubin < 3 x ULN for age
CRE < 3 x ULN for age
4) Written consent to participate in this clinical trial has been given by the subject in person or by a legal guardian (when the subject is younger than 20 years at consent).

#: Severe complications or intractable synptoms on this study are conditions that consist systemically or locally lesions of vascular anomalies and require treatments. If they don't perform treatment, it will cause obvious problems or they will have poor outcomes treated with conventional therapy (surgery, sclerotherapy).

1) Patients who currently have an uncontrolled infection
2) Uncontrolled diabetes, uncontrolled hypertension, uncontrolled hyperlipidemia, chronic liver disease, or chronic renal disease and bleeding that needs frequent transfusion
3) History of allergy to sirolimus, or additive substance
4) Patients with primary or secondary immunodeficiency, or patients who may have a risk of severe infection after administration of sirolimus*
5) Patients who have undergone surgical resection or interventional radiology procedures for target lesions within 2 weeks
6) Pregnant, probably pregnant, or breast-feeding woman.
Patients who do not agree birth control during clinical trial.
7) Patient who is judged inappropriate to participate in this study by the investigators
8) Less than PS score 20

*: The immunodeficiency refer to condition in which there is a congenital or secondary immunodeficiency state, which may be worsened by sirolimus administration or clearly increase the risk of infection. Specifically, if the white blood cell count or immunoglobulin count is low due to malnutrition, immunosuppressive therapy, protein leakage at administration of sirolimus. Or the patients have a histry of sepsis or infection.

+:If patients don't violate the exclusion criteria but have poor general condition, or it is difficult to determine the indication for treatment, the eligibility of this study should be discussed by the investigators.

Both

Intractable vascular anomalies

Body surface area (BSA) >= 1.0m2: an initial dose of sirolimus (2mg/day) is single orally administered under fed or fasting condition. Subsequently, the sirolimus dosage is adjusted to achieve trough levels between 5-15 ng/mL.
BSA < 1.0m2: an initial dose of sirolimus (1mg/day) is single orally administered under fed or fasting condition. Subsequently, the sirolimus dosage is adjusted to achieve trough levels between 5-15 ng/mL. Maximum dose of sirolimus is 4 mg per day.

Vascular disorders

114

Adverse effects and side effects

Target lesion response rate determined by Independent Review Facility after 24, 52 weeks and every 24 weeks of treatments
Respiratory function after 24, 52 weeks and every 24 weeks of treatments
Evaluation of pleural effusion after 24, 52 weeks and every 24 weeks of treatments
Evaluation of ascites after 24, 52 weeks and every 24 weeks of treatments
Blood coagulation parameters after 5, 12, 24, 52 weeks and every 24 weeks of treatments
Bleeding after 24, 52 weeks and every 24 weeks of treatments
Pain after 24, 52 weeks and every 24 weeks of treatments
QOL improvement rates after 24 and 52 weeks of treatments
ADL improvement rates after 24, 52 weeks and every 24 weeks of treatments
Laboratory values
Vital signs
Pharmacokinetics

+81-3-3416-0181

Feb. 06, 2019

none