<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04406870</url>
  </required_header>
  <id_info>
    <org_study_id>PRL-SRL-IHHE</org_study_id>
    <nct_id>NCT04406870</nct_id>
  </id_info>
  <brief_title>Sirolimus in the Treatment for Infantile Hepatic Hemangioendothelioma(IEEH)</brief_title>
  <acronym>PRL-SRL-IHHE</acronym>
  <official_title>Sirolimus in the Treatment for Propranolol-resistant Infantile Hepatic Hemangioendothelioma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Shanghai Children's Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Shanghai Children's Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Infantile hepatic hemangioendothelioma (IHHE) is an infantile hemangioma involving the&#xD;
      liver.Since 2008, propranolol has been used for the treatment of hemangioma, and some&#xD;
      researchers have also started to report the use of propranolol for the treatment of infantile&#xD;
      hepatic hemangioma in children. Sirolimus can be used in patients with vascular malformations&#xD;
      such as hemangiomas. IHHE is also an infantile hemangioma involving the liver,thus sirolimus&#xD;
      may paly the role in treatment of IHHE.The clinical trial explores the efficacy of sequential&#xD;
      treatment of sirolimus to refractory IHHE patients resistant with propranolol, to improve the&#xD;
      therapeutic effect, reduce the side effects of traditional treatment methods (hormones,&#xD;
      interferon), and reduce the number of operations and interventions and to provide a clinical&#xD;
      basis for the application of the new therapeutics model of IHHE of &quot;propranolol + sequential&#xD;
      sirolimus treatment&quot;.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      According to the World Health Organization(WHO) classification of digestive system tumors in&#xD;
      the fourth edition in 2010, infantile hepatic hemangioendothelioma (IHHE) is an infantile&#xD;
      hemangioma involving the liver. It is a benign tumor, which can be subgrouped into focal,&#xD;
      multifocal, and diffusing in children, as well as combining vascular malformations of the&#xD;
      skin, brain, digestive tract and other organs.Since 2008, propranolol has been used for the&#xD;
      treatment of hemangioma, and some researchers have also started to report the use of&#xD;
      propranolol for the treatment of infantile hepatic hemangioma in children.And more and more&#xD;
      clinicians unanimously recommend propranolol as first-line medication for the treatment of&#xD;
      IHHE.However, there are few solutions to propranolol-resistant IHHE. Sirolimus is a&#xD;
      serine/threonine kinase which plays a pivotal role in cell mortality, angiogenesis and cell&#xD;
      growth. Sirolimus can be used in patients with vascular malformations such as hemangiomas.&#xD;
      Children with vascular malformations received 0.1mg/kg of sirolimus orally every day and&#xD;
      maintained the blood concentration at 8-15ng/ml. The lesions gradually disappear with time&#xD;
      going on. Therefore, sirolimus can be used as a second-line medicine for refractory&#xD;
      hemangioma and vascular malformation.Interestingly, the investigator's previous study which&#xD;
      is retrospective analysis of 30 patients has indicated the effective rate of propranolol&#xD;
      alone in treating infantile hepatic endothelial tumor (IHHE) was 57.7%, while that of&#xD;
      sequential treatment combined with sirolimus was 84.6%.So, this clinical trial is going to&#xD;
      explore the efficacy of sequential treatment of sirolimus to refractory IHHE patients&#xD;
      resistant with propranolol,to improve the therapeutic effect,furtherly, reduce the side&#xD;
      effects of traditional treatment methods (hormones, interferon), as well as the number of&#xD;
      operations and interventions and to provide a clinical guide for the novel therapeutics model&#xD;
      of propranolol combined with sirolimus for sequential treatment of infantile hepatic&#xD;
      hemangioendothelioma.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Not yet recruiting</overall_status>
  <start_date type="Anticipated">July 2020</start_date>
  <completion_date type="Anticipated">June 30, 2025</completion_date>
  <primary_completion_date type="Anticipated">June 30, 2024</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Recruiting patients with IHHE who have no response to propranolol after 3 months. Then propranolol combined with sirolimus will be given.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change of tumor size</measure>
    <time_frame>1 month</time_frame>
    <description>measuring the tumor size by ultrasound</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change of PIVKA-II</measure>
    <time_frame>1 month</time_frame>
    <description>Using PIVKA-II assay kit (ARCHITECT I2000SR REFURB, Abbott, America).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change of alpha-1 fetoprotein (AFP)</measure>
    <time_frame>1 month</time_frame>
    <description>Using the AFP assay kit (ARCHITECT AFP, Abbott, America).</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">36</enrollment>
  <condition>Hemangioendothelioma of Liver</condition>
  <arm_group>
    <arm_group_label>Intervention</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>patients with propranolol-resistant IHHE are given propranolol combined with sirolimus</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sirolimus Oral Product</intervention_name>
    <description>Patients with IHHE wil be treated with propranolol (1 mg / kg , twice a day, after meals), and then evaluation will be performed after 3 months (changes of the tumor size measured by ultrasound examination, and changes of tumor volume measured by abdominal enhancement CT).It will be admitted into the group once the tumor volume shrinks &lt;30%.Then propanolol combined with sirolimus will be given. Propranolol will be given at 1mg/kg,twice a day and sirolimus will be given at 0.8mg/m²(body surface area), twice a day. Recording and doing assessment of tumor size, adverse effects as well as complicated symptoms.</description>
    <arm_group_label>Intervention</arm_group_label>
    <other_name>TORISEL</other_name>
    <other_name>rapamycin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>propranolol</intervention_name>
    <description>Patients with IHHE wil be treated with propranolol (1 mg / kg , twice a day, after meals), and then evaluation will be performed after 3 months (changes of the tumor size measured by ultrasound examination, and changes of tumor volume measured by abdominal enhancement CT).It will be admitted into the group once the tumor volume shrinks &lt;30%.Then propanolol combined with sirolimus will be given. Propranolol will be given at 1mg/kg,twice a day and sirolimus will be given at 0.8mg/m²(body surface area), twice a day. Recording and doing assessment of tumor size, adverse effects as well as complicated symptoms.</description>
    <arm_group_label>Intervention</arm_group_label>
    <other_name>xin de an (chinese name means making me comfortable)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Confirmed as IHHE&#xD;
&#xD;
          -  Age between 1 month and 36 months&#xD;
&#xD;
          -  Receiving propranolol for 3 months but the tumor size shrinks &lt;30%&#xD;
&#xD;
          -  With written informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Confirmed as hepatoblastoma&#xD;
&#xD;
          -  Have accepted surgical resection&#xD;
&#xD;
          -  Clinical data missing&#xD;
&#xD;
          -  Patients with Kasabach-Merritt phenomenon&#xD;
&#xD;
          -  Receiving propranolol for 3 months and the tumor size shrinks &gt;30%&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Month</minimum_age>
    <maximum_age>36 Months</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Song Gu, Doctor</last_name>
    <role>Study Chair</role>
    <affiliation>Shanghai Children's Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Song Gu, Doctor</last_name>
    <phone>+86-18930830716</phone>
    <email>gusong@shsmu.edu.cn</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Hongxiong Gao, Master</last_name>
    <phone>+86-15216606578</phone>
    <email>guyafeihong@163.com</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Shanghai Children's Medical Center Shanghai Jiaotong University School of Medicine</name>
      <address>
        <city>Shanghai</city>
        <state>Shanghai</state>
        <zip>200127</zip>
        <country>China</country>
      </address>
    </facility>
    <contact>
      <last_name>Song Gu, Doctor</last_name>
    </contact>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <reference>
    <citation>Requena L, Kutzner H. Hemangioendothelioma. Semin Diagn Pathol. 2013 Feb;30(1):29-44. doi: 10.1053/j.semdp.2012.01.003.</citation>
    <PMID>23327728</PMID>
  </reference>
  <reference>
    <citation>Chatmethakul T, Bhat R, Alkaabi M, Siddiqui A, Peevy K, Zayek M. Infantile Hepatic Hemangioendothelioma: An Uncommon Cause of Persistent Pulmonary Hypertension in a Newborn Infant. AJP Rep. 2016 Jul;6(3):e260-3. doi: 10.1055/s-0036-1585578.</citation>
    <PMID>27468364</PMID>
  </reference>
  <reference>
    <citation>Chen CC, Kong MS, Yang CP, Hung IJ. Hepatic hemangioendothelioma in children: analysis of thirteen cases. Acta Paediatr Taiwan. 2003 Jan-Feb;44(1):8-13.</citation>
    <PMID>12800377</PMID>
  </reference>
  <reference>
    <citation>Mehrabi A, Kashfi A, Schemmer P, Sauer P, Encke J, Fonouni H, Friess H, Weitz J, Schmidt J, Buchler MW, Kraus TW. Surgical treatment of primary hepatic epithelioid hemangioendothelioma. Transplantation. 2005 Sep 27;80(1 Suppl):S109-12. doi: 10.1097/01.tp.0000186904.15029.4a.</citation>
    <PMID>16286886</PMID>
  </reference>
  <reference>
    <citation>Maaloul I, Aloulou H, Hentati Y, Kamoun T, Mnif Z, Hachicha M. Infantile hepatic hemangioendothelioma successfully treated by low dose of propranolol. Presse Med. 2017 Apr;46(4):454-456. doi: 10.1016/j.lpm.2017.01.010. Epub 2017 Mar 15. No abstract available.</citation>
    <PMID>28318668</PMID>
  </reference>
  <reference>
    <citation>Chaturvedi K, Steinberg JS, Snyder CS. Cost-effectiveness of treating infantile haemangioma with propranolol in an outpatient setting. Cardiol Young. 2018 Oct;28(10):1105-1108. doi: 10.1017/S1047951118000987. Epub 2018 Jul 26.</citation>
    <PMID>30047346</PMID>
  </reference>
  <reference>
    <citation>Avagyan S, Klein M, Kerkar N, Demattia A, Blei F, Lee S, Rosenberg HK, Arnon R. Propranolol as a first-line treatment for diffuse infantile hepatic hemangioendothelioma. J Pediatr Gastroenterol Nutr. 2013 Mar;56(3):e17-20. doi: 10.1097/MPG.0b013e31824e50b7. No abstract available.</citation>
    <PMID>22331019</PMID>
  </reference>
  <reference>
    <citation>Ozdemir ZC, Duzenli Kar Y, Sohret NC, Kebapci M, Bor O. Beta blocker and steroid therapy in the treatment of infantile hepatic hemangioendothelioma. Drug Discov Ther. 2017 Jul 31;11(3):161-164. doi: 10.5582/ddt.2017.01025. Epub 2017 Jul 25.</citation>
    <PMID>28652510</PMID>
  </reference>
  <verification_date>May 2020</verification_date>
  <study_first_submitted>May 17, 2020</study_first_submitted>
  <study_first_submitted_qc>May 23, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 29, 2020</study_first_posted>
  <last_update_submitted>May 23, 2020</last_update_submitted>
  <last_update_submitted_qc>May 23, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">May 29, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>propranolol-resistant</keyword>
  <keyword>sirolimus</keyword>
  <keyword>infantile hepatic hemangioendothelioma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hemangioendothelioma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sirolimus</mesh_term>
    <mesh_term>Propranolol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04406870
org study id: PRL-SRL-IHHE
nct id: NCT04406870
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
Infantile hepatic hemangioendothelioma (IHHE) is an infantile hemangioma involving the
      liver.Since 2008, propranolol has been used for the treatment of hemangioma, and some
      researchers have also started to report the use of propranolol for the treatment of infantile
      hepatic hemangioma in children. Sirolimus can be used in patients with vascular malformations
      such as hemangiomas. IHHE is also an infantile hemangioma involving the liver,thus sirolimus
      may paly the role in treatment of IHHE.The clinical trial explores the efficacy of sequential
      treatment of sirolimus to refractory IHHE patients resistant with propranolol, to improve the
      therapeutic effect, reduce the side effects of traditional treatment methods (hormones,
      interferon), and reduce the number of operations and interventions and to provide a clinical
      basis for the application of the new therapeutics model of IHHE of "propranolol + sequential
      sirolimus treatment".
According to the World Health Organization(WHO) classification of digestive system tumors in
      the fourth edition in 2010, infantile hepatic hemangioendothelioma (IHHE) is an infantile
      hemangioma involving the liver. It is a benign tumor, which can be subgrouped into focal,
      multifocal, and diffusing in children, as well as combining vascular malformations of the
      skin, brain, digestive tract and other organs.Since 2008, propranolol has been used for the
      treatment of hemangioma, and some researchers have also started to report the use of
      propranolol for the treatment of infantile hepatic hemangioma in children.And more and more
      clinicians unanimously recommend propranolol as first-line medication for the treatment of
      IHHE.However, there are few solutions to propranolol-resistant IHHE. Sirolimus is a
      serine/threonine kinase which plays a pivotal role in cell mortality, angiogenesis and cell
      growth. Sirolimus can be used in patients with vascular malformations such as hemangiomas.
      Children with vascular malformations received 0.1mg/kg of sirolimus orally every day and
      maintained the blood concentration at 8-15ng/ml. The lesions gradually disappear with time
      going on. Therefore, sirolimus can be used as a second-line medicine for refractory
      hemangioma and vascular malformation.Interestingly, the investigator's previous study which
      is retrospective analysis of 30 patients has indicated the effective rate of propranolol
      alone in treating infantile hepatic endothelial tumor (IHHE) was 57.7%, while that of
      sequential treatment combined with sirolimus was 84.6%.So, this clinical trial is going to
      explore the efficacy of sequential treatment of sirolimus to refractory IHHE patients
      resistant with propranolol,to improve the therapeutic effect,furtherly, reduce the side
      effects of traditional treatment methods (hormones, interferon), as well as the number of
      operations and interventions and to provide a clinical guide for the novel therapeutics model
      of propranolol combined with sirolimus for sequential treatment of infantile hepatic
      hemangioendothelioma.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Recruiting patients with IHHE who have no response to propranolol after 3 months. Then propranolol combined with sirolimus will be given.
primary purpose: Treatment
masking: None (Open Label)
measure: Change of tumor size
time frame: 1 month
description: measuring the tumor size by ultrasound
measure: Change of PIVKA-II
time frame: 1 month
description: Using PIVKA-II assay kit (ARCHITECT I2000SR REFURB, Abbott, America).
measure: Change of alpha-1 fetoprotein (AFP)
time frame: 1 month
description: Using the AFP assay kit (ARCHITECT AFP, Abbott, America).
arm group label: Intervention
arm group type: Experimental
description: patients with propranolol-resistant IHHE are given propranolol combined with sirolimus
intervention type: Drug
intervention name: Sirolimus Oral Product
description: Patients with IHHE wil be treated with propranolol (1 mg / kg , twice a day, after meals), and then evaluation will be performed after 3 months (changes of the tumor size measured by ultrasound examination, and changes of tumor volume measured by abdominal enhancement CT).It will be admitted into the group once the tumor volume shrinks <30%.Then propanolol combined with sirolimus will be given. Propranolol will be given at 1mg/kg,twice a day and sirolimus will be given at 0.8mg/m²(body surface area), twice a day. Recording and doing assessment of tumor size, adverse effects as well as complicated symptoms.
arm group label: Intervention
other name: TORISEL
other name: rapamycin
intervention type: Drug
intervention name: propranolol
description: Patients with IHHE wil be treated with propranolol (1 mg / kg , twice a day, after meals), and then evaluation will be performed after 3 months (changes of the tumor size measured by ultrasound examination, and changes of tumor volume measured by abdominal enhancement CT).It will be admitted into the group once the tumor volume shrinks <30%.Then propanolol combined with sirolimus will be given. Propranolol will be given at 1mg/kg,twice a day and sirolimus will be given at 0.8mg/m²(body surface area), twice a day. Recording and doing assessment of tumor size, adverse effects as well as complicated symptoms.
arm group label: Intervention
other name: xin de an (chinese name means making me comfortable)
criteria: 
gender: All
minimum age: 1 Month
maximum age: 36 Months
healthy volunteers: No
last name: Song Gu, Doctor
role: Study Chair
affiliation: Shanghai Children's Medical Center
last name: Song Gu, Doctor
phone: +86-18930830716
email: gusong@shsmu.edu.cn
last name: Hongxiong Gao, Master
phone: +86-15216606578
email: guyafeihong@163.com
facility: 
contact: 
country: China
citation: Requena L, Kutzner H. Hemangioendothelioma. Semin Diagn Pathol. 2013 Feb;30(1):29-44. doi: 10.1053/j.semdp.2012.01.003.
PMID: 23327728
citation: Chatmethakul T, Bhat R, Alkaabi M, Siddiqui A, Peevy K, Zayek M. Infantile Hepatic Hemangioendothelioma: An Uncommon Cause of Persistent Pulmonary Hypertension in a Newborn Infant. AJP Rep. 2016 Jul;6(3):e260-3. doi: 10.1055/s-0036-1585578.
PMID: 27468364
citation: Chen CC, Kong MS, Yang CP, Hung IJ. Hepatic hemangioendothelioma in children: analysis of thirteen cases. Acta Paediatr Taiwan. 2003 Jan-Feb;44(1):8-13.
PMID: 12800377
citation: Mehrabi A, Kashfi A, Schemmer P, Sauer P, Encke J, Fonouni H, Friess H, Weitz J, Schmidt J, Buchler MW, Kraus TW. Surgical treatment of primary hepatic epithelioid hemangioendothelioma. Transplantation. 2005 Sep 27;80(1 Suppl):S109-12. doi: 10.1097/01.tp.0000186904.15029.4a.
PMID: 16286886
citation: Maaloul I, Aloulou H, Hentati Y, Kamoun T, Mnif Z, Hachicha M. Infantile hepatic hemangioendothelioma successfully treated by low dose of propranolol. Presse Med. 2017 Apr;46(4):454-456. doi: 10.1016/j.lpm.2017.01.010. Epub 2017 Mar 15. No abstract available.
PMID: 28318668
citation: Chaturvedi K, Steinberg JS, Snyder CS. Cost-effectiveness of treating infantile haemangioma with propranolol in an outpatient setting. Cardiol Young. 2018 Oct;28(10):1105-1108. doi: 10.1017/S1047951118000987. Epub 2018 Jul 26.
PMID: 30047346
citation: Avagyan S, Klein M, Kerkar N, Demattia A, Blei F, Lee S, Rosenberg HK, Arnon R. Propranolol as a first-line treatment for diffuse infantile hepatic hemangioendothelioma. J Pediatr Gastroenterol Nutr. 2013 Mar;56(3):e17-20. doi: 10.1097/MPG.0b013e31824e50b7. No abstract available.
PMID: 22331019
citation: Ozdemir ZC, Duzenli Kar Y, Sohret NC, Kebapci M, Bor O. Beta blocker and steroid therapy in the treatment of infantile hepatic hemangioendothelioma. Drug Discov Ther. 2017 Jul 31;11(3):161-164. doi: 10.5582/ddt.2017.01025. Epub 2017 Jul 25.
PMID: 28652510
responsible party type: Sponsor
mesh term: Hemangioendothelioma
mesh term: Sirolimus
mesh term: Propranolol
sharing ipd: No