Efficacy and Safety of Different Concentrations of Sirolimus in the Treatment of Kaposiform Hemangioendothelioma.

Study Overview
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Brief Summary
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The purpose of this study is to compare the efficacy and safety of different concentration gradients of sirolimus in the treatment of Kaposiform hemangioendothelioma.

Detailed Description
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Kaposiform hemangioendothelioma (KHE) is a rare aggressive vascular neoplasm that occurs predominantly in infancy or early childhood, with an incidence of approximately 0.71/100,000. Currently, sirolimus is a promising treatment modality for KHE. Most scholars consider sirolimus blood concentration of 5-15 ng/ml to be an effective therapeutic concentration. However, long-term higher dose sirolimus treatment can cause some common complications such as oral mucositis which affects the quality of life of the patient. Finer control of the plasma concentration of sirolimus may contribute to the efficacy of treatment and reduce the incidence of complications. Therefore, we conducted this study to see if low-dose sirolimus is beneficial to the prognosis of patients.

Official Title
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Different Doses of Sirolimus for Kaposiform Hemangioendothelioma: a Randomized Clinical Trial

Conditions
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Kaposiform Hemangioendothelioma

Intervention / Treatment
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* Drug: Sirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Presenting a KHE with the following characteristics: Male and female; Between 0 and 14 years of age; KHE diagnosis was confirmed by local investigators and by consensus of our multidisciplinary vascular anomaly group at the West China Hospital of Sichuan University based on: Biopsy; Compatible MRI findings; History and clinical features. The multidisciplinary vascular anomaly group was a collaboration team that included vascular anomaly experts in pediatric surgery, plastic surgery, pediatric dermatology, pathology and radiology. Without KMP, which was defined as a platelet count of less than 100×10^9/L, with consumptive coagulopathy and hypofibrinogenemia. Patients were required to have adequate liver, renal and bone marrow function, and absence of active infection Consent of parents (or the person with parental authority in families): signed and dated written informed consent. Exclusion Criteria: Patients contraindicated for the administration of sirolimus (e.g., those with an allergy to sirolimus or other rapamycin analog) Exposure to chemotherapy, embolization, corticosteroids, propranolol, sclerotherapy or any other investigational agents within 1 weeks before enrolment on study; Patients had a history of a major surgery within 2 weeks before enrollment; Patients who have a history of treatment with sirolimus or other mTOR inhibitor; Any known evidence of significant local or systemic uncontrolled infection, defined as receiving intravenous antibiotics at the time of enrollment; Concurrent severe and/or uncontrolled medical diseases that could compromise participation in the study (e.g. uncontrolled diabetes, uncontrolled hypertension, severe malnutrition, chronic liver or renal disease, active upper gastrointestinal tract ulceration). Impairment of gastrointestinal function or chronic gastrointestinal disease that may significantly alter the absorption of sirolimus. Patients with inadequate liver function: Total bilirubin higher than or equal to 1.5 × the upper limit of the normal (ULN) for age and alanine aminotransferase and aspartate aminotransferase higher than or equal to 2.5 × the ULN for age. Patients with inadequate renal function: 0-5 years of age maximum serum creatinine (mg/dL) of 0.8; 6-10 years of age maximum serum creatinine (mg/dL) of 1.0; 11-14 years of age maximum serum creatinine (mg/dL) of 1.2; Adequate bone marrow function: Absolute neutrophil count lower than 1 × 109/L; History of a malignancy within 5 years; HIV infection or known immunodeficiency; Indication for treatment with corticosteroids, vincristine, interferon-α, sirolimus, or tacrolimus for an indication other than IH; Patients with an inability to participate in or follow-up during the study treatment and assessment plan; Inability to give informed consent.

Ages Eligible for Study
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Minimum Age: 1 Day
Maximum Age: 14 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low dose of sirolimus<br>Sirolimus The plasma trough concentration of sirolimus is maintained within the range of 5-8 ng/ml by adjusting sirolimus dose, for 1 year. | Drug: Sirolimus<br>* Use of different doses of the same drug<br>* Other names: Rapamune;|
| Active Comparator: Regular dose of sirolimus<br>Sirolimus The plasma trough concentration of sirolimus is maintained within the range of 10-15 ng/ml by adjusting sirolimus dose, for 1 year. | Drug: Sirolimus<br>* Use of different doses of the same drug<br>* Other names: Rapamune;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients achieving an objective response at month 12 | Objective response was defined as ≥20% reduction in KHE volume compared to that at baseline. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| lesion responses | The primary endpoint was classified as follow: Complete involution: 100% resolution of the measured KHE; Nearly complete involution was defined as decrease of ≥75% and <100%; Partial involution was defined as decrease of ≥20% and <75%; No change was defined as <20% increase and <20% decrease in the volumes of KHE lesions; Further growth was defined as ≥20% increase in the volume of index KHE compared with the baseline volume measured. Lesion responses were overall lesion response rate and good lesion response rate. Overall lesion response comprised complete, nearly complete and partial involutions. Good lesion response comprised complete and nearly complete involutions. | 12 months | 
| Quality of life (QOL) in patients | Pediatric Quality of Life Inventory (PedsQLTM) 4.0 Genetic Core Infant Scales (<2 years) or Pediatric Quality of Life Inventory (PedsQLTM) 4.0 Genetic Core Scales (2-18 years) were used. | 12 months | 
| Disease sequelae | Disease sequelae (e.g., chronic pain, lymphedema and decreased ROM) were assessed by site investigators at month 12. The site investigators assessed patients' extremity swelling (if any), general physical activity and exercise levels. The diagnosis of lymphedema was based on physical examination (e.g., Stemmer's sign) and lymphoscintigraphic findings. | 12 months | 
| Frequency of adverse events | Frequency of adverse events (e.g. gastrointestinal disorders, blood and lymphatic system disorders, metabolic disorders or other abnormal laboratory results, skin disorders and general disorders, etc.) collected by investigator and reported by parents. All adverse events were collected and graded according to Common Terminology Criteria for Adverse Events, version 5.0 (CTCAE v5.0). The causality of the adverse event was determined by the multidisciplinary staff and was classified as definitively not related, probably not related, possibly related, probably related, or definitively related. Any dose reductions, interruptions, or cessations enacted at the discretion of the investigators were recorded. | 12 months | 
| The changes of fibrinogen and D-dimer levels | Fibrinogen and D-dimer levels | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kaposiform Hemangioendothelioma, Sirolimus, Efficacy, Safety