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Sirolimus Plus Propranolol Versus Sirolimus Plus Prednisolone for Kaposiform Hemangioendothelioma

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ClinicalTrials.gov Identifier: NCT03188068
Recruitment Status : Recruiting
First Posted : June 15, 2017
Last Update Posted : July 23, 2019
Sponsor:
Information provided by (Responsible Party):
Yi Ji, West China Hospital

Tracking Information
First Submitted Date  ICMJE June 9, 2017
First Posted Date  ICMJE June 15, 2017
Last Update Posted Date July 23, 2019
Actual Study Start Date  ICMJE June 1, 2017
Estimated Primary Completion Date January 1, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 12, 2017)
  • The changes of platelet counts [ Time Frame: 2 months ]
    Platelet counts
  • The changes of fibrinogen levels [ Time Frame: 2 months ]
    Fibrinogen levels
  • The changes in KHE volume [ Time Frame: 6 and 12 months ]
    Response to therapy was measured by volumetric magnetic resonance imaging (MRI) analyses were performed at baseline and 6 and 12 months after treatment and were independently assessed by 2 radiologists. Changes in KHE size 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 mixed KHE were taken at months 0, 6 and 12 by a medical photographer.
  • The changes in the patient's symptoms and/or complications. [ Time Frame: 6 and 12 months ]
    Improvement in the range of motion.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03188068 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 12, 2017)
  • Frequency of adverse events [ Time Frame: 12 months ]
    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 4.0 (CTCAE v4.0). 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.
  • Change in blood biomarkers [ Time Frame: 6 and 12 months ]
    Change in vascular endothelial growth factor (VEGF-A, C and D), IL-6, IL-8, angiopoietin 1 and 2. These parameters were measured via a series of correlative laboratory studies using blood samples.
  • Quality of life (QOL) in patients. [ Time Frame: 12 months ]
    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.
  • Measuring the impact of KHE on family functioning. [ Time Frame: 12 months ]
    PedsQLTM 4.0 Family Impact Module (FIM) was used.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Sirolimus Plus Propranolol Versus Sirolimus Plus Prednisolone for Kaposiform Hemangioendothelioma
Official Title  ICMJE Sirolimus Plus Propranolol Versus Sirolimus Plus Prednisolone for Kaposiform Hemangioendothelioma With Kasabach-Merritt Syndrome
Brief Summary

Kaposiform hemangioendothelioma (KHE) is a rare vascular neoplasm that occurs predominantly in infancy or early childhood. KHE has a nearly equal sex ratio. The annual incidence of KHE has been estimated at 0.071 per 100,000 children. KHE presents with intermediate-malignant and locally aggressive characteristics but without distant metastases.

This pilot trial studies sirolimus versus sirolimus plus pednisolone in treating patients diagnosed with kaposiform hemangioendothelioma (KHE) and Kasabach-Merritt phenomemon (KMP) that cannot be removed by surgery. The purpose of this study is to compare the efficacy and safety of orally administered sirolimus versus sirolimus plus pednisolone in the treatment of KHE associated with KMP.

Detailed Description

Kasabach-Merritt phenomemon (KMP) is a profound thrombocytopenia resulting from intralesional platelet trapping. It is now clear that KMP occurs with KHE and tufted angioma, not with infantile or congenital hemangiomas. KMP is typically associated with more aggressive lesions and poorer outcomes. Clinically significant KMP is a severe thrombocytopenia, generally below 30× 109/L. Severe thrombocytopenia may indicate a severer tumor, a progressive tumor, partially or totally insensitive to therapy. In addition to severe, persistent thrombocytopenia characteristic of KMP, patients often manifest elevated D-dimer and low fibrinogen. Coagulopathy in addition to thrombocytopenia is associated with more aggressive presentations and may indicate current infection or inflammation. Additionally, KMP may be complicated by severe anemia due to blood sequestration and intra-lesional hemorrhaging. KHE with KMP have notably high morbidity and mortality rates, resulting predominantly from rapid tumor growth and infiltration, compression or destruction of vital structures, and hemodynamic instability.

Consensus treatment guidelines from a multidisciplinary expert panel were published in 2013. Medical treatments with corticosteroids and/or vincristine have been recommended for the management of KHE. However, first-line treatment with corticosteroids is successful in only 10-27% of all cases, and treatment with vincristine is successful in 60-70% of patients. Moreover, vincristine monotherapy has not been confirmed to provide significant benefits in critically ill patients.

Sirolimus (also known as rapamycin) is an inhibitor of the mammalian target of rapamycin (mTOR). In recent studies, sirolimus was shown to be effective in patients with complex vascular anomalies, including KHE. Our multicenter, retrospective study demonstrated that oral sirolimus is an effective and safe option for the treatment of progressive KHE. Additionally, our data emphasized that the KHE treatment regimen should be tailored to individual patients and guided by specific clinical circumstances. In cases of severe Kasabach-Merritt phenomenon (KMP), sirolimus in combination with the short-term administration of prednisolone is recommended for controlling life-threatening conditions.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Kaposiform Hemangioendothelioma
  • Kasabach Merritt Phenomenon
Intervention  ICMJE
  • Drug: Sirolimus
    Oral administration
    Other Name: Rapamycin
  • Drug: Prednisolone
    Oral administered with sirolimus
  • Drug: Propranolol
    Oral administered with sirolimus
Study Arms  ICMJE
  • Active Comparator: Sirolimus plus propranolol

    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.

    Propranolol was initiated at a dosage of 1 mg/kg per day divided 3 times daily for 1 week, and then increased to 2 mg/kg per day divided 3 times daily from weeks 2.

    Interventions:
    • Drug: Sirolimus
    • Drug: Propranolol
  • Active Comparator: Sirolimus plus prednisolone

    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.

    Prednisolone was administered 2 mg/kg administered once daily. Should satisfactory clinical responses and hematologic stabilization ensue, prednisolone may be tapered and discontinued within the following 4-6 weeks.

    Interventions:
    • Drug: Sirolimus
    • Drug: Prednisolone
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 12, 2017)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 1, 2020
Estimated Primary Completion Date January 1, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Presenting a KHE with the following characteristics:

    1. Clinical features and histological findings consistent with progressive, non-resectable KHE associated with KMP.
    2. Patients must be 0 - 18 years of age at the time of study entry.
    3. Without functional impairment requiring treatment of corticosteroid.
  • Organ function requirements:

    1 Adequate liver function:

    1. Total bilirubin less than or equal to 1.5 x upper limit of normal (ULN)for age, and
    2. ALT and AST less than or equal to 2.5 x upper limit normal (ULN) for age.

    2 Adequate renal function:

    1. 0-5 years of age maximum serum creatinine (mg/dL) of 0.8
    2. 6-10 years of age maximum serum creatinine (mg/dL) of 1.0
    3. 11-15 years of age maximum serum creatinine (mg/dL) of 1.2
    4. 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.
  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 18 Years   (Child, Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Yi Ji, MD, PhD 86 28 85423453 jijiyuanyuan@163.com
Contact: Siyuan Chen, MD, PhD 86 28 85422215 siy_chen@163.com
Listed Location Countries  ICMJE China
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03188068
Other Study ID Numbers  ICMJE 2017-312
81401606 ( Other Grant/Funding Number: National Natural Science Foundation of China )
81400862 ( Other Grant/Funding Number: National Natural Science Foundation of China )
2015SU04A15 ( Other Grant/Funding Number: Excellent Youth Scholars of Sichuan University )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Yi Ji, West China Hospital
Study Sponsor  ICMJE West China Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Yi Ji, MD, PhD West China Hospital
PRS Account West China Hospital
Verification Date July 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP