Efficacy and Safety of Sirolimus to Vascular Anomalies

Efficacy and Safety of Sirolimus in the Treatment of the Complicated Vascular Anomalies

To evaluate the safety and efficacy of Sirolimus in complicated vascular anomalies in Chinese children

Study Overview

• Status: Completed
• Conditions: Vascular Anomaly
• Intervention / Treatment: Drug: Sirolimus

Detailed Description

Vascular anomalies are composed of vascular tumors and vascular malformations. The prognosis of vascular anomalies is significantly variable. Most of them had a benign course. However, complicated vascular anomalies can lead to disfigurement, organ disfunction and life-threatening with significant morbidity and mortality. Traditional treatments, including steroids, vincristine, cyclophosphamide and surgery, had limited response to complicated vascular anomalies. In the past few years, the inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway-sirolimus has emerged as a treatment for severe vascular anomalies. Besides, preclinical studies also showed that the Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mTOR pathway play an important role in the development of vascular tumors and vascular malformations. However, the exact efficacious rate and complications of sirolimus are still unknow in china because of the lack of large scale of prospective studies. Therefore, it's important to perform this prospective study to determine the safety and efficacy of sirolimus in the treatment of Chinese children with complicated vascular anomalies, and this study will also make contributions to the diagnoses and treatments of vascular anomalies.

• Study Type: Interventional
• Enrollment (Actual): 126
• Phase: Not Applicable

Contacts and Locations

Study Locations

• China
  • Sichuan
    • Chengdu, Sichuan, China, 61004·
      • West China Hospital of Sichuan University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 second to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• All patients included in the present research must be diagnosed with one of the following vascular anomalies:

  1. Kaposiform Hemangioendotheliomas without Kasabach-Merritt Phenomenon
  2. Tufted Angioma without Kasabach-Merritt Phenomenon
  3. Capillary Malformations
  4. Lymphatic Malformations
  5. Venous Malformations
  6. Capillary-Venous Malformation (CVM)
  7. Capillary-Lymphatic Malformation (CLM)
  8. Lymphatic-Venous Malformation (LVM)
  9. Capillary-Lymphatic-Venous Malformation (CLVM)
  10. Multifocal Lymphangiomatosis and Thrombocytopenia (MLT)
• Patients must be 0 - 18 years of age at the time of study entry.
• Without functional impairment requiring treatment of corticosteroid.
• Organ function requirements:
• Adequate liver function Total bilirubin less than or equal to 1.5 x upper limit of normal (ULN)for age, and alanine transaminase (ALT) and aspartate aminotransferase (AST) less than or equal to 2.5 x upper limit normal (ULN) for age.
• Adequate 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 11-15 years of age maximum serum creatinine (mg/dL) of 1.2 16-18 years of age maximum serum creatinine (mg/dL) of 1.5
• Adequate bone marrow function:

Absolute Neutrophil Count (ANC) greater than or equal to 1 x 10 to the ninth/Liter

• Consent of parents (or the person having parental authority in families): Signed and dated written informed consent.

Exclusion Criteria:

• Allergy to sirolimus or other rapamycin analogues.
• Allergy to sirolimus or other rapamycin analogues.
• Any known evidence of significant local or systemic uncontrolled infection, defined as receiving intravenous antibiotics at the time of randomization.
• Patients must not be known to be Human Immunodeficiency Virus positive or known immunodeficiency. Testing is not required unless a condition is suspected.
• Other concurrent severe and/or uncontrolled medical disease which 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 who have a history of malignancy.
• Patients with an inability to participate or to follow the study treatment and assessment plan.
• Patients who have a history of treatment with sirolimus or other mTOR inhibitor.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sirolimus	Drug: Sirolimus; Sirolimus was initiated at a dosage of 0.8 mg/m2 administered twice daily. Subsequently, the sirolimus dosage was adjusted monthly to achieve trough levels between 10 and 15 ng/mL.; Other Names: Rapamycin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Volumetric changes in complicated vascular anomalies to sirolimus	Response to sirolimus treatment was measured by volumetric magnetic resonance imaging (MRI) analyses, which were performed at baseline and 6 and 12 months after treatment and were independently assessed by 2 radiologists. Changes in size of vascular anomalies were classified as further growth (increase of ≥10%), no change (<10% increase and <10% decrease), partial involution (decrease of ≥10% and <75%), nearly complete involution (decrease of ≥75% and <100%), or complete involution (100%). Photographs of the complicated vascular anomalies were taken at months 0, 3, 6 and 12 by a medical photographer. Complete/nearly complete resolution of the vascular anomalies at month 12 compared to baseline based on the intra-patient blinded centralized independent qualitative assessments of month 12 MRI.	Baseline, 6, and 12 months
The changes in the patient's symptoms and/or complications.		Baseline, 3, 6, and 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of Life in patients by the Pediatric Quality of Life Inventory TM (PedsQLTM) 4.0 Generic Core Scales.	The PedsQL 4.0 Generic Core Scales encompass: 1) Physical Functioning (8 items), 2) Emotional Functioning (5 items), 3) Social Functioning (5 items), and 4) School Functioning (5 items), and were developed through focus groups and cognitive interviews. The PedsQL 4.0 Generic Core Scales are comprised of parallel child self-report (ages 5-18) and parent proxy-report formats (ages 0-18). A 5-point response scale is utilized across child self-report for ages 8 to 18 and parent proxy-report (0=never a problem; 1=almost never a problem; 2=sometimes a problem; 3=often a problem; 4=almost always a problem). For patients between ages 5-7, the response scale is simplified to a 3-point scale (0=not at all a problem; 2=sometimes a problem; 4=a lot of a problem. Items are reverse-scored and linearly transformed to a 0 to 100 scale (0=100, 1=75, 2 =50, 3=25, 4=0). Scale Scores are computed as the sum of the items divided by the number of items answered.	Baseline, 6, 12 months
Measuring the impact of vascular anomalies on family functioning by PedsQLTM 4.0 Family Impact Module (FIM).		Baseline, 6, 12 months
Frequency of adverse events as assessed by CTCAE v4.0		Baseline, 3, 6, 12 months
Changes in plasma levels fibrinogen and/ or D-dimers		Baseline, 3, 6, 12 months

Collaborators and Investigators

• Sponsor: West China Hospital
• Investigators: Principal Investigator: Yi Ji, West China Hospital

Publications and helpful links

General Publications

• Ji Y, Chen S, Yang K, Zhou J, Zhang X, Jiang X, Xu X, Lu G, Qiu L, Kong F, Zhang Y. A prospective multicenter study of sirolimus for complicated vascular anomalies. J Vasc Surg. 2021 Nov;74(5):1673-1681.e3. doi: 10.1016/j.jvs.2021.04.071. Epub 2021 May 31.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2018
• Primary Completion (Actual): February 19, 2021
• Study Completion (Actual): February 19, 2021

Study Registration Dates

• First Submitted: June 17, 2018
• First Submitted That Met QC Criteria: June 28, 2018
• First Posted (Actual): July 11, 2018

Study Record Updates

• Last Update Posted (Actual): March 15, 2022
• Last Update Submitted That Met QC Criteria: March 12, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Sirolimus; Vascular anomalies
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Cardiovascular Abnormalities; Congenital Abnormalities; Vascular Malformations; Physiological Effects of Drugs; Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Sirolimus
• Other Study ID Numbers: 2018-618

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No