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Kaposiform HemangioendotheliomaPhase 4NCT04448873

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

A Phase 4 study testing Sirolimus in people with Kaposiform Hemangioendothelioma and Kasabach-Merritt Syndrome, run by Children's Hospital of Fudan University at 1 site in China.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

This randomized controlled trial aims to compare guided discontinuation with maintenance treatment of sirolimus in pediatric patients with KHE. Read more about this study

Who is it for?
Ages Up to 12 years
What is being tested?
Sirolimus
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
1 siteChina
Study dates
1 Jul 2020to 1 Jul 2023
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Up to 12 years
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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)

Who cannot join

  • 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

Trial locations and contacts

1 site in 1 country.

China1 site
  • Children's Hospital of Fudan University

    Shanghai, Shanghai Municipality, 210012

Other trials in China

About this study

Official title: 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.

Read the 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.

Being tested
Sirolimus
Keywords
Kaposiform Hemangioendothelioma, Kasabach-Merritt Syndrome, Sirolimus, Rapamycin
Medical subject headings
Kaposiform Hemangioendothelioma, Kasabach-Merritt Syndrome

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • SirolimusDrug

    Also called Rapamycin

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

Study groups in NCT04448873
Study groupRoleWhat they receive
Maintenance treatment groupActive comparatorAfter 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.
Receives: Drug: Sirolimus
Guided discontinuation groupExperimentalAfter at least 2 years of remission of KHE, the discontinuation measurement should be guided by the clinician with the following principles: 1. 10% monthly reduction of the previous dose at most. 2. At least 5 half-lives between each reduction (2 weeks). 3. Blood concentration should be monitored monthly. Adjustment can be suggested according to the linear relationship between the dose and the blood concentration. 4. At least 6 months for the duration of guided discontinuation. 5. 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.
Receives: Drug: Sirolimus

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Remission of KHE and no use of sirolimus at one year follow-up.

    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.

    Measured: From admission to follow-up one year

Secondary outcomes (7)
  1. Remission of KHE and the dose of sirolimus at one year follow-up

    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.

    Measured: From admission to follow-up one year

  2. Relapse of KHE and the dose of sirolimus at one year follow-up

    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.

    Measured: From admission to follow-up one year

  3. Side effects of sirolimus

    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.

    Measured: From admission to follow-up one year

  4. Platelet count

    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.

    Measured: From admission to follow-up one year

  5. Fibrinogen level

    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.

    Measured: From admission to follow-up one year

  6. Tumor volume

    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.

    Measured: From admission to follow-up one year

  7. Complaints

    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.

    Measured: From admission to follow-up one year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Jun 2020
  2. Study start1 Jul 2020
  3. Primary completion1 Feb 2023
  4. Study completion1 Jul 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
30 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04448873
Sponsor's protocol ID
LK200421
Status last verified
Sep 2023
First submitted
10 May 2020
Last updated
26 Sep 2023
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No

Publications

  • 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.

    PubMed 31489702
  • 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.

    PubMed 20730884
  • 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.

    PubMed 28976859
  • 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.

    PubMed 22871490
  • 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.

    PubMed 30054848
  • 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.

    PubMed 28027747
  • 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.

    PubMed 18094377
  • 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.

    PubMed 26041743
  • 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.

    PubMed 29442540
  • 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.

    PubMed 28962668
  • 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.

    PubMed 31452734
  • 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.

    PubMed 10823378
  • 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.

    PubMed 24476346
  • 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.

    PubMed 31087627
  • 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.

    PubMed 28526601

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Sirolimus in people with Kaposiform Hemangioendothelioma and Kasabach-Merritt Syndrome, run by Children's Hospital of Fudan University at 1 site in China.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 6 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Remission of KHE and no use of sirolimus at one year follow-up. (time frame: From admission to follow-up one year). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04448873, which also lists 15 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Sep 2023.

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