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Trial record 32 of 36 for:    "Viral Infectious Disease" | "Everolimus"

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

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.


Condition or disease Intervention/treatment Phase
Kaposiform Hemangioendothelioma Kasabach Merritt Phenomenon Drug: Sirolimus Drug: Prednisolone Drug: Propranolol Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Sirolimus Plus Propranolol Versus Sirolimus Plus Prednisolone for Kaposiform Hemangioendothelioma With Kasabach-Merritt Syndrome
Actual Study Start Date : June 1, 2017
Estimated Primary Completion Date : January 1, 2020
Estimated Study Completion Date : January 1, 2020


Arm Intervention/treatment
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.

Drug: Sirolimus
Oral administration
Other Name: Rapamycin

Drug: Propranolol
Oral administered with sirolimus

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.

Drug: Sirolimus
Oral administration
Other Name: Rapamycin

Drug: Prednisolone
Oral administered with sirolimus




Primary Outcome Measures :
  1. The changes of platelet counts [ Time Frame: 2 months ]
    Platelet counts

  2. The changes of fibrinogen levels [ Time Frame: 2 months ]
    Fibrinogen levels

  3. 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.


  4. The changes in the patient's symptoms and/or complications. [ Time Frame: 6 and 12 months ]
    Improvement in the range of motion.


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. 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.

  4. Measuring the impact of KHE on family functioning. [ Time Frame: 12 months ]
    PedsQLTM 4.0 Family Impact Module (FIM) was used.



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Ages Eligible for Study:   up to 18 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03188068


Contacts
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Contact: Yi Ji, MD, PhD 86 28 85423453 jijiyuanyuan@163.com
Contact: Siyuan Chen, MD, PhD 86 28 85422215 siy_chen@163.com

Locations
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China, Sichuan
West China Hospital of Sichuan University Recruiting
Chengdu, Sichuan, China, 610041
Contact: Yi Ji, MD, PhD    +86 28 85423453    jijiyuanyuan@163.com   
Contact: Siyuan Chen, MD, PhD    +86 28 85423460    siy_chen@163.com   
Principal Investigator: Yi Ji, MD, PhD         
Sub-Investigator: Bo Xiang, MD, PhD         
Sub-Investigator: Zhicheng Xu, MD, PhD         
Sub-Investigator: Fuyu Li, MD         
Sub-Investigator: Xiaoping Jiang, MD         
Sub-Investigator: Lin Zhong, MD         
Sub-Investigator: Yuan Li, MD, PhD         
Sub-Investigator: Siyuan Chen, MD, PhD         
Sub-Investigator: Yanan Li, MD         
Sub-Investigator: Chuan Wang, MD         
Sub-Investigator: Qi Wang, MD         
Sub-Investigator: Kaiying Yang, MD         
Sponsors and Collaborators
West China Hospital
Investigators
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Principal Investigator: Yi Ji, MD, PhD West China Hospital

Publications:
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Responsible Party: Yi Ji, Principal Investigator, West China Hospital
ClinicalTrials.gov Identifier: NCT03188068     History of Changes
Other Study ID Numbers: 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 )
First Posted: June 15, 2017    Key Record Dates
Last Update Posted: July 23, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Keywords provided by Yi Ji, West China Hospital:
Kaposiform Hemangioendothelioma
Kasabach Merritt Phenomenon
Sirolimus
Prednisolone
Additional relevant MeSH terms:
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DNA Virus Infections
Virus Diseases
Everolimus
Sarcoma, Kaposi
Hemangioendothelioma
Kasabach-Merritt Syndrome
Hemangioma
Neoplasms, Vascular Tissue
Neoplasms by Histologic Type
Neoplasms
Herpesviridae Infections
Sarcoma
Neoplasms, Connective and Soft Tissue
Thrombocytopenia
Blood Platelet Disorders
Hematologic Diseases
Sirolimus
Prednisolone
Methylprednisolone Acetate
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone acetate
Propranolol
Prednisolone hemisuccinate
Prednisolone phosphate
Anti-Bacterial Agents
Anti-Infective Agents
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents