- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT04448873
Guided Discontinuation Versus Maintenance Treatment of Sirolimus in Pediatric Patients With Kaposiform Hemangioendothelioma
September 24, 2023 updated by: Children's Hospital of Fudan University
Guided Discontinuation Versus Maintenance Treatment of Sirolimus in Pediatric Patients With Kaposiform Hemangioendothelioma: a Randomized Controlled Trial
This randomized controlled trial aims to compare guided discontinuation with maintenance treatment of sirolimus in pediatric patients with KHE.
Study Overview
Status
Completed
Intervention / Treatment
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 Type
Interventional
Enrollment (Actual)
30
Phase
- Phase 4
Contacts and Locations
This section provides the contact details for those conducting the study, and information on where this study is being conducted.
Study Locations
-
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Shanghai
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Shanghai, Shanghai, China, 210012
- Children's Hospital of Fudan University
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Participation Criteria
Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.
Eligibility Criteria
Ages Eligible for Study
No older than 12 years (Child)
Accepts Healthy Volunteers
No
Description
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
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / 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.
|
After at least 2 years of remission of KHE, we compare guided discontinuation with maintenance treatment in pediatric patients with KHE.
Other Names:
|
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:
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. |
After at least 2 years of remission of KHE, we compare guided discontinuation with maintenance treatment in pediatric patients with KHE.
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Remission of KHE and no use of sirolimus at one year follow-up.
Time Frame: 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.
|
From admission to follow-up one year
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Remission of KHE and the dose of sirolimus at one year follow-up
Time Frame: 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.
|
From admission to follow-up one year
|
Relapse of KHE and the dose of sirolimus at one year follow-up
Time Frame: 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.
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From admission to follow-up one year
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Side effects of sirolimus
Time Frame: 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.
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From admission to follow-up one year
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Platelet count
Time Frame: 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.
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From admission to follow-up one year
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Fibrinogen level
Time Frame: 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.
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From admission to follow-up one year
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Tumor volume
Time Frame: 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.
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From admission to follow-up one year
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Complaints
Time Frame: 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.
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From admission to follow-up one year
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Remission of KHE and no use of sirolimus at two or three year follow-up
Time Frame: 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.
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From admission to follow-up two and three years
|
Remission of KHE and the dose of sirolimus at two or three year follow-up
Time Frame: 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.
|
From admission to follow-up two and three years
|
Relapse of KHE and the dose of sirolimus at two or three year follow-up
Time Frame: 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.
|
From admission to follow-up two and three years
|
Collaborators and Investigators
This is where you will find people and organizations involved with this study.
Investigators
- Principal Investigator: Kai Li, MD, PhD, Children's Hospital of Fudan University
Publications and helpful links
The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.
General Publications
- MacDonald A, Scarola J, Burke JT, Zimmerman JJ. Clinical pharmacokinetics and therapeutic drug monitoring of sirolimus. Clin Ther. 2000;22 Suppl B:B101-121. doi: 10.1016/s0149-2918(00)89027-x.
- Wang Z, Yao W, Sun H, Dong K, Ma Y, Chen L, Zheng S, Li K. Sirolimus therapy for kaposiform hemangioendothelioma with long-term follow-up. J Dermatol. 2019 Nov;46(11):956-961. doi: 10.1111/1346-8138.15076. Epub 2019 Sep 5.
- Blatt J, Stavas J, Moats-Staats B, Woosley J, Morrell DS. Treatment of childhood kaposiform hemangioendothelioma with sirolimus. Pediatr Blood Cancer. 2010 Dec 15;55(7):1396-8. doi: 10.1002/pbc.22766.
- Mauri L, D'Agostino RB Sr. Challenges in the Design and Interpretation of Noninferiority Trials. N Engl J Med. 2017 Oct 5;377(14):1357-1367. doi: 10.1056/NEJMra1510063. No abstract available.
- Croteau SE, Liang MG, Kozakewich HP, Alomari AI, Fishman SJ, Mulliken JB, Trenor CC 3rd. Kaposiform hemangioendothelioma: atypical features and risks of Kasabach-Merritt phenomenon in 107 referrals. J Pediatr. 2013 Jan;162(1):142-7. doi: 10.1016/j.jpeds.2012.06.044. Epub 2012 Aug 4.
- Schmid I, Klenk AK, Sparber-Sauer M, Koscielniak E, Maxwell R, Haberle B. Kaposiform hemangioendothelioma in children: a benign vascular tumor with multiple treatment options. World J Pediatr. 2018 Aug;14(4):322-329. doi: 10.1007/s12519-018-0171-5. Epub 2018 Jul 27.
- Ryu YJ, Choi YH, Cheon JE, Kim WS, Kim IO, Park JE, Kim YJ. Imaging findings of Kaposiform Hemangioendothelioma in children. Eur J Radiol. 2017 Jan;86:198-205. doi: 10.1016/j.ejrad.2016.11.015. Epub 2016 Nov 10.
- Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, Margreiter R, Hugo C, Grinyo JM, Frei U, Vanrenterghem Y, Daloze P, Halloran PF; ELITE-Symphony Study. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007 Dec 20;357(25):2562-75. doi: 10.1056/NEJMoa067411.
- Gianfreda D, Nicastro M, Galetti M, Alberici F, Corradi D, Becchi G, Baldari G, De Filippo M, Ferretti S, Moroni G, Foti R, Di Gangi M, Jeannin G, Saffroy R, Emile JF, Buzio C, Vaglio A. Sirolimus plus prednisone for Erdheim-Chester disease: an open-label trial. Blood. 2015 Sep 3;126(10):1163-71. doi: 10.1182/blood-2015-01-620377. Epub 2015 Jun 3.
- Brahmer JR, Lacchetti C, Schneider BJ, Atkins MB, Brassil KJ, Caterino JM, Chau I, Ernstoff MS, Gardner JM, Ginex P, Hallmeyer S, Holter Chakrabarty J, Leighl NB, Mammen JS, McDermott DF, Naing A, Nastoupil LJ, Phillips T, Porter LD, Puzanov I, Reichner CA, Santomasso BD, Seigel C, Spira A, Suarez-Almazor ME, Wang Y, Weber JS, Wolchok JD, Thompson JA; National Comprehensive Cancer Network. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2018 Jun 10;36(17):1714-1768. doi: 10.1200/JCO.2017.77.6385. Epub 2018 Feb 14.
- Sturup AE, Jensen HD, Dolmer S, Birk M, Albert N, Nielsen M, Hjorthoj C, Eplov L, Ebdrup BH, Mors O, Nordentoft M. TAILOR - tapered discontinuation versus maintenance therapy of antipsychotic medication in patients with newly diagnosed schizophrenia or persistent delusional disorder in remission of psychotic symptoms: study protocol for a randomized clinical trial. Trials. 2017 Sep 29;18(1):445. doi: 10.1186/s13063-017-2172-4.
- Wang D, Chen X, Li Z. Population pharmacokinetics of sirolimus in pediatric patients with kaposiform hemangioendothelioma: A retrospective study. Oncol Lett. 2019 Sep;18(3):2412-2419. doi: 10.3892/ol.2019.10562. Epub 2019 Jul 4.
- Holt DW, Mandelbrot DA, Tortorici MA, Korth-Bradley JM, Sierka D, Levy DI, See Tai S, Horowitz GL. Long-term evaluation of analytical methods used in sirolimus therapeutic drug monitoring. Clin Transplant. 2014 Feb;28(2):243-51. doi: 10.1111/ctr.12305. Epub 2014 Jan 30.
- Mariani LG, Schmitt IR, Garcia CD, Kiszewski AE. Low dose sirolimus treatment for refractory tufted angioma and congenital kaposiform hemangioendothelioma, both with Kasabach-Merritt phenomenon. Pediatr Blood Cancer. 2019 Aug;66(8):e27810. doi: 10.1002/pbc.27810. Epub 2019 May 14. No abstract available.
- Mizuno T, Emoto C, Fukuda T, Hammill AM, Adams DM, Vinks AA. Model-based precision dosing of sirolimus in pediatric patients with vascular anomalies. Eur J Pharm Sci. 2017 Nov 15;109S:S124-S131. doi: 10.1016/j.ejps.2017.05.037. Epub 2017 May 17.
Study record dates
These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.
Study Major Dates
Study Start (Actual)
July 1, 2020
Primary Completion (Actual)
February 1, 2023
Study Completion (Actual)
July 1, 2023
Study Registration Dates
First Submitted
May 10, 2020
First Submitted That Met QC Criteria
June 24, 2020
First Posted (Actual)
June 26, 2020
Study Record Updates
Last Update Posted (Actual)
September 26, 2023
Last Update Submitted That Met QC Criteria
September 24, 2023
Last Verified
September 1, 2023
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Virus Diseases
- Infections
- Neoplasms, Connective and Soft Tissue
- Neoplasms by Histologic Type
- Neoplasms
- Hematologic Diseases
- DNA Virus Infections
- Thrombocytopenia
- Blood Platelet Disorders
- Herpesviridae Infections
- Sarcoma
- Hemangioma
- Neoplasms, Vascular Tissue
- Sarcoma, Kaposi
- Hemangioendothelioma
- Kasabach-Merritt Syndrome
- 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
- LK200421
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
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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