Guided Discontinuation Versus Maintenance Treatment of Sirolimus in Pediatric Patients With Kaposiform Hemangioendothelioma

Sponsor

Children's Hospital of Fudan University (Other)

Overall Status

Recruiting

CT.gov ID

NCT04448873

Collaborator

(none)

Enrollment

Location

Arms

Anticipated Duration (Months)

0.8

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This randomized controlled trial aims to compare guided discontinuation with maintenance treatment of sirolimus in pediatric patients with KHE.

Condition or Disease	Intervention/Treatment	Phase
Kaposiform Hemangioendothelioma Kasabach-Merritt Syndrome	Drug: Sirolimus	Phase 4

Detailed Description

Kaposiform Hemangioendothelioma (KHE) is a rare vascular tumor that occurs in infants and children. KHE is characterized by sheets of spindle cells with an infiltrative pattern in the dermis, subcutaneous fat, and muscle. It is locally aggressive and can cause Kasabach-Merritt phenomenon, a serious life-threatening coagulopathy characterized by profound thrombocytopenia and hypofibrinogenemia. Sirolimus, one of the mTOR inhibitors, has become a new and very effective treatment, which is especially reliable for KHE with KMP and has acceptable side effects. However, there is yet no strong evidence on the best practice of treatment length of sirolimus. This randomized controlled trial aims to compare guided discontinuation with maintenance treatment in pediatric patients with KHE in order to provide a basis for the optimal treatment duration of sirolimus, as well as the clinical characteristics of pediatric patients who can safely reduce the dose till withdrawal.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

30 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Single (Outcomes Assessor)

Masking Description:

Only the outcome assessors are blinded, neither clinicians nor patients, because they should be attentive of the risk of relapse in the discontinuation group. Also, it seems unethical if researchers were not to discover the group of patients in the maintenance group who can discontinue sirolimus without relapsing. Clinicians should be given the possibility to adjust dose and ensure the benefits of patients. Therefore, this trial only includes assessors blinding.

Primary Purpose:

Treatment

Official Title:

Guided Discontinuation Versus Maintenance Treatment of Sirolimus in Pediatric Patients With Kaposiform Hemangioendothelioma: a Randomized Controlled Trial

Actual Study Start Date :

Jul 1, 2020

Anticipated Primary Completion Date :

Dec 1, 2022

Anticipated Study Completion Date :

Jul 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Maintenance treatment group After at least 2 years of remission of KHE, the participant receives sirolimus as usual. The serum concentration is supposed to be 5-7 ng/ml. If the effect or side effects of sirolimus require discontinuation, it is allowed to modify intervention, and if so, the patient stays in the maintenance group.	Drug: Sirolimus After at least 2 years of remission of KHE, we compare guided discontinuation with maintenance treatment in pediatric patients with KHE. Other Names: Rapamycin
Experimental: Guided discontinuation group After at least 2 years of remission of KHE, the discontinuation measurement should be guided by the clinician with the following principles: 10% monthly reduction of the previous dose at most. At least 5 half-lives between each reduction (2 weeks). Blood concentration should be monitored monthly. Adjustment can be suggested according to the linear relationship between the dose and the blood concentration. At least 6 months for the duration of guided discontinuation. Regular assessments and evaluations should be done. If the condition relapses or worsens during this process, dose of sirolimus should be adjusted to the previously effective dose. After a 3-month stabilization phase, 5% monthly reduction of the previous dose could be considered.	Drug: Sirolimus After at least 2 years of remission of KHE, we compare guided discontinuation with maintenance treatment in pediatric patients with KHE. Other Names: Rapamycin

Arm

Intervention/Treatment

Active Comparator: Maintenance treatment group

After at least 2 years of remission of KHE, the participant receives sirolimus as usual. The serum concentration is supposed to be 5-7 ng/ml. If the effect or side effects of sirolimus require discontinuation, it is allowed to modify intervention, and if so, the patient stays in the maintenance group.

Drug: Sirolimus

After at least 2 years of remission of KHE, we compare guided discontinuation with maintenance treatment in pediatric patients with KHE.

Other Names:

Rapamycin

Experimental: Guided discontinuation group

After at least 2 years of remission of KHE, the discontinuation measurement should be guided by the clinician with the following principles: 10% monthly reduction of the previous dose at most. At least 5 half-lives between each reduction (2 weeks). Blood concentration should be monitored monthly. Adjustment can be suggested according to the linear relationship between the dose and the blood concentration. At least 6 months for the duration of guided discontinuation. Regular assessments and evaluations should be done. If the condition relapses or worsens during this process, dose of sirolimus should be adjusted to the previously effective dose. After a 3-month stabilization phase, 5% monthly reduction of the previous dose could be considered.

Drug: Sirolimus

After at least 2 years of remission of KHE, we compare guided discontinuation with maintenance treatment in pediatric patients with KHE.

Other Names:

Rapamycin

Outcome Measures

Primary Outcome Measures

Remission of KHE and no use of sirolimus at one year follow-up. [From admission to follow-up one year]
The primary outcome is a binary variable. The primary outcome measure will be analyzed with binary logistic regression to estimate the odds ratio between the two groups.

Secondary Outcome Measures

Remission of KHE and the dose of sirolimus at one year follow-up [From admission to follow-up one year]
At one year's follow-up, the participant may be on remission, but still taking sirolimus. The condition is a binary variable and the dose of sirolimus is a continuous variable.
Relapse of KHE and the dose of sirolimus at one year follow-up [From admission to follow-up one year]
At one year's follow-up, the participant may suffer from relapse of KHE and still takes sirolimus. The period of time to the first relapse will be recorded as a time variable, and the cox regression survival analysis model will be used.The dose of sirolimus is a continuous variable. Whether this variable is normally distributed will be checked.
Side effects of sirolimus [From admission to follow-up one year]
The outcome 4 will be described. Adverse events will be reported according to Common Terminology Criteria for Adverse Events, version 4.0 (CTCAE v4.0). Incidence of complications such as oral ulcers, abnormal liver enzymes, infections will be recorded. The blood concentration of sirolimus will be adjusted accordingly.
Platelet count [From admission to follow-up one year]
Platelet count is one of the major indicators of response to treatment and will be used in a prognosis model to predict the clinical characteristics of patients with benefits. It is supposed to be greater than 100×10^9/L.
Fibrinogen level [From admission to follow-up one year]
Fibrinogen level will be used in a prognosis model to predict the clinical characteristics of patients with benefits. It is supposed to be at 2-4g/L.
Tumor volume [From admission to follow-up one year]
Tumor volume will be used in a prognosis model to predict the clinical characteristics of patients with benefits. The size of the tumor is supposed to shrink according to imaging evaluation. The tumor is supposed to be softer by palpation.
Complaints [From admission to follow-up one year]
Complaints are subjective feelings. Whether there is pain, swelling, lameness or skin color change will be recorded as binary variables and used in a prognosis model to predict the clinical characteristics of patients with benefits.

Other Outcome Measures

Remission of KHE and no use of sirolimus at two or three year follow-up [From admission to follow-up two and three years]
This outcome is a binary variable. The primary outcome measure will be analyzed with binary logistic regression to estimate the odds ratio between the two groups.
Remission of KHE and the dose of sirolimus at two or three year follow-up [From admission to follow-up two and three years]
At two or three years' follow-up, the participant may be on remission, but still taking sirolimus. The condition is a binary variable and the dose of sirolimus is a continuous variable.
Relapse of KHE and the dose of sirolimus at two or three year follow-up [From admission to follow-up two and three years]
At two or three years' follow-up, the participant may suffer from relapse of KHE and still takes sirolimus. The period of time to the relapse will be recorded as a time variable, and the cox regression survival analysis model will be used.The dose of sirolimus is a continuous variable. Whether this variable is normally distributed will be checked.

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 12 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Participant diagnosed with KHE with or without KMP
Participant age 0-12 years
Participant with detailed medical records of the disease at the time of screening
Participant with at least two years of remission of KHE and no previous toxicity or adverse events
Participant with normal liver and kidney function
Participant with signed and dated informed consent from the guardian(s)

Exclusion Criteria:

Participant with other hematological diseases
Participant with other solid tumor
Participant with general disease such as hypertension, diabetes, adrenal insufficiency, neurological diseases, liver and kidney dysfunction, and cardiopulmonary insufficiency.
Participant with infectious diseases
Unwilling participant