<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/NCT04423237</url>
  </required_header>
  <id_info>
    <org_study_id>1105/2015</org_study_id>
    <nct_id>NCT04423237</nct_id>
  </id_info>
  <brief_title>Risk Factors and Measures to Prevent Liver and Pancreas Complications in Pediatric Patients After HSCT</brief_title>
  <official_title>Identification of Risk Factors and Measures to Prevent Liver and Pancreas Complications in Pediatric Patients Undergoing a Hematopoietic Stem Cell Transplant (HSCT)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Pisa</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>IRCCS Burlo Garofolo</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Genova</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pisa</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Hematopoietic Stem Cell Transplantation (HSCT) is currently a standard procedure for a wide&#xD;
      range of blood-oncological diseases and genetic disorders. Recent improvements in transplant&#xD;
      technologies, infection prevention and graft-versus-host-disease (GVHD) management procedures&#xD;
      have significantly reduced the transplant-related mortality (TRM). However, approximately 50%&#xD;
      of pediatric patients may develop liver dysfunction before HSCT and 74% to 85.5% after HSCT,&#xD;
      with a TRM related to liver dysfunction reaching 46%. The liver and pancreas complications&#xD;
      still remain too high for the difficulties and diagnostic inefficiencies and, consequently,&#xD;
      for the lack of targeted and safer therapies. The diagnostic problems can be summarized in 3&#xD;
      major points: a) the histological examination of liver and pancreas parenchyma cannot be&#xD;
      routinely performed because of the organ anatomy and the relative risk of the bioptic&#xD;
      procedures; b) the lack of specific biomarkers or advanced imaging techniques appropriate for&#xD;
      the diagnosis of HSCT complications; c) the multifactorial causes of organ complications, as&#xD;
      well as drug toxicities, GVHD, siderosis, ductopenia (considered as an index of hepatic&#xD;
      GVHD), the accumulation of potentially toxic substances favored by siderosis and ductopenia.&#xD;
      In more than 50% of HSCT patients, siderosis and/or ductopenia may represent common&#xD;
      pathological conditions. Furthermore, international guidelines issued by onco-hematology and&#xD;
      transplantation scientific societies recommend a chelating treatment with deferasirox in all&#xD;
      hematological and oncological patients undergoing an intense transfusion regimen. However, in&#xD;
      the presence of siderosis and marked ductopenia, patients receiving deferasirox may&#xD;
      experience both severe renal and hematological toxicities and lack of effectiveness of the&#xD;
      chelating treatment.&#xD;
&#xD;
      Therefore, the principal aim of the present retrospective study will be the evaluation of the&#xD;
      transplant-related mortality (TRM) in patients requiring a chelation treatment according to&#xD;
      the Italian guidelines in pediatric patients&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The present retrospective study will be conducted at the Bone Marrow Transplant Center, IRCCS&#xD;
      Burlo Garofolo, Trieste, Italy. All pediatric patients who underwent one or more allogeneic&#xD;
      HSCTs between 2010 and 2018 will be enrolled according to inclusion/exclusion criteria.&#xD;
&#xD;
      The following data will be collected in a retrospective manner:&#xD;
&#xD;
        -  Data on the underlying disease (diagnosis, therapeutic protocol, transfusion regimen,&#xD;
           possible relapses, type of transplant, conditioning regimen, infectious complications,&#xD;
           immunosuppressive treatment, including use of steroids);&#xD;
&#xD;
        -  Pre-transplant liver and pancreatic function, as well as quantification of iron content&#xD;
           by nuclear magnetic resonance (MRI);&#xD;
&#xD;
        -  Pre-transplant histological evaluation of liver parenchyma in case of pre-existing liver&#xD;
           disease;&#xD;
&#xD;
        -  Post-transplant liver and pancreatic function and the evaluation of parenchymal&#xD;
           accumulation of Fe+;&#xD;
&#xD;
        -  Length and doses of DFX treatment, and corresponding drug plasma concentrations as per&#xD;
           routine drug monitoring protocols;&#xD;
&#xD;
        -  Treatment tolerability according to CTC-AE grading V5.0, November 27, 2017 The&#xD;
           post-transplant data will be collected within 2 years from HSCT (or the last HSCT when&#xD;
           more than one).&#xD;
&#xD;
      The data entered in an appropriate anonymous database will be processed by descriptive&#xD;
      statistics and uni- multivariate statistical analyses according to study endpoints. DFX&#xD;
      plasma concentrations will be analyzed by means of to a nonlinear mixed effect modeling&#xD;
      approach to elaborate a population pharmacokinetic (POP/PK) model. POP/PK findings will be&#xD;
      further analyzed together with clinical and laboratory data.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 30, 2020</start_date>
  <completion_date type="Anticipated">June 30, 2022</completion_date>
  <primary_completion_date type="Actual">June 30, 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Retrospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Transplant-related mortality (TRM)</measure>
    <time_frame>0-24 months after transplant</time_frame>
    <description>TRM in SIO/SIO+D patients treated with deferasirox as per Italian guidelines</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Post-HSCT liver and pancreatic complications</measure>
    <time_frame>0-24 months after transplant</time_frame>
    <description>Incidence of post-HSCT liver and pancreatic complications in SIO/SIO+D patients treated with deferasirox as per Italian guidelines</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to iron concentration normalization</measure>
    <time_frame>0-24 months after transplant</time_frame>
    <description>The times required for the normalization of the Iron Concentration in SIO and SIO+D patients</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Statistical analysis of risk factors for ductopenia</measure>
    <time_frame>0-24 months after transplant</time_frame>
    <description>The correlation between ductopenia and potential risk factors will be investigated by uni- and multi-variate analyses. The following data will be included in the analyses as potential risk factors: chemo-radiotherapy regimens prior to HSCT (drugs and doses), number of blood transfusions</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minimum plasma concentrations of deferasirox</measure>
    <time_frame>0-24 months after transplant</time_frame>
    <description>In SIO/SIO+D patients, a factorial analysis for mixed data and a nonlinear mixed effect modeling approach will be used to investigate plasma pharmacokinetics of deferasirox in terms of patients' exposure (minimum plasma concentration, Cmin) and to evaluate the effect of identified covariates on drug disposition.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation of minimum plasma concentrations of deferasirox with drug tolerability</measure>
    <time_frame>0-24 months after transplant</time_frame>
    <description>In SIO/SIO+D patients, uni- and multi-variate analyses will be adopted to assess the correlation of Cmin with treatment tolerability</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Actual">39</enrollment>
  <condition>Iron Overload</condition>
  <arm_group>
    <arm_group_label>Severe Iron Overload (SIO)</arm_group_label>
    <description>Children affected by Severe Iron Overload who received DEFERASIROX</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Severe Iron Overload + Ductopenia (SIO+D)</arm_group_label>
    <description>Children affected by Severe Iron Overload + Ductopenia who received DEFERASIROX</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Deferasirox</intervention_name>
    <description>DEFERASIROX administered as per clinical practice and according to technical note</description>
    <arm_group_label>Severe Iron Overload (SIO)</arm_group_label>
    <arm_group_label>Severe Iron Overload + Ductopenia (SIO+D)</arm_group_label>
    <other_name>Exjade or Deferasirox Milan</other_name>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Pediatric inpatients who a) underwent a HSCT at the Bone Marrow Transplant Center, IRCCS&#xD;
        Burlo Garofalo, and b) had a ≥2-year follow-up after transplant. All procedures were&#xD;
        performed according to clinical routine protocols&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  one or more allogeneic HSCT&#xD;
&#xD;
          -  any type of disease (blood-oncological or genetic), from any type of donor (sibling,&#xD;
             MUD, haploidentical) and with any source of stem cells (spinal cord, peripheral blood&#xD;
             stem cells, cord blood)&#xD;
&#xD;
          -  diagnosis of moderate-to-severe siderosis (by nuclear magnetic resonance imaging, MRI)&#xD;
             and who needed a chelation treatment with deferasirox&#xD;
&#xD;
          -  one or more liver biopsies in the post-transplant period to perform histological&#xD;
             examinations&#xD;
&#xD;
          -  Complete results from lab analyses&#xD;
&#xD;
          -  2-year follow-up after HSCT&#xD;
&#xD;
          -  therapeutic drug monitoring (TDM) protocol for deferasirox plasma concentration as per&#xD;
             clinical routine&#xD;
&#xD;
          -  Sign of the informed consent by the parents or legal representatives&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Lack of liver biopsies after transplantation, results from laboratory analyses or TDM&#xD;
             or MRI&#xD;
&#xD;
          -  Lack of informed consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>17 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Natalia Maximova, MD</last_name>
    <role>Study Director</role>
    <affiliation>Institute for Maternal and Child Health, IRCCS Burlo Garofalo, Trieste, Italy</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>IRCCS Burlo Garofolo</name>
      <address>
        <city>Trieste</city>
        <zip>34137</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Italy</country>
  </location_countries>
  <reference>
    <citation>Oshrine B, Lehmann LE, Duncan CN. Safety and utility of liver biopsy after pediatric hematopoietic stem cell transplantation. J Pediatr Hematol Oncol. 2011 Apr;33(3):e92-7. doi: 10.1097/MPH.0b013e3182025236.</citation>
    <PMID>21317809</PMID>
  </reference>
  <reference>
    <citation>Locasciulli A, Testa M, Valsecchi MG, Vecchi L, Longoni D, Sparano P, Rovelli A, Uderzo C, Masera G, Alberti A. Morbidity and mortality due to liver disease in children undergoing allogeneic bone marrow transplantation: a 10-year prospective study. Blood. 1997 Nov 1;90(9):3799-805.</citation>
    <PMID>9345068</PMID>
  </reference>
  <reference>
    <citation>Quaglia A, Duarte R, Patch D, Ngianga-Bakwin K, Dhillon AP. Histopathology of graft versus host disease of the liver. Histopathology. 2007 May;50(6):727-38. doi: 10.1111/j.1365-2559.2007.02679.x.</citation>
    <PMID>17493237</PMID>
  </reference>
  <reference>
    <citation>Gandon Y, Olivie D, Guyader D, Aube C, Oberti F, Sebille V, Deugnier Y. Non-invasive assessment of hepatic iron stores by MRI. Lancet. 2004 Jan 31;363(9406):357-62. doi: 10.1016/S0140-6736(04)15436-6.</citation>
    <PMID>15070565</PMID>
  </reference>
  <reference>
    <citation>Maximova N, Zanon D, Pascolo L, Zennaro F, Gregori M, Grosso D, Sonzogni A. Metal accumulation in the renal cortex of a pediatric patient with sickle cell disease: a case report and review of the literature. J Pediatr Hematol Oncol. 2015 May;37(4):311-4. doi: 10.1097/MPH.0000000000000322.</citation>
    <PMID>25811747</PMID>
  </reference>
  <verification_date>January 2022</verification_date>
  <study_first_submitted>May 30, 2020</study_first_submitted>
  <study_first_submitted_qc>June 4, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 9, 2020</study_first_posted>
  <last_update_submitted>January 4, 2022</last_update_submitted>
  <last_update_submitted_qc>January 4, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">January 5, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Pisa</investigator_affiliation>
    <investigator_full_name>Antonello Di Paolo, M.D., Ph.D.</investigator_full_name>
    <investigator_title>Associated Professor</investigator_title>
  </responsible_party>
  <keyword>iron overload</keyword>
  <keyword>deferasirox</keyword>
  <keyword>children</keyword>
  <keyword>HSCT</keyword>
  <keyword>toxicity</keyword>
  <keyword>ductopenia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Iron Overload</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Deferasirox</mesh_term>
  </intervention_browse>
  <!-- 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/NCT04423237
org study id: 1105/2015
nct id: NCT04423237
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Hematopoietic Stem Cell Transplantation (HSCT) is currently a standard procedure for a wide
      range of blood-oncological diseases and genetic disorders. Recent improvements in transplant
      technologies, infection prevention and graft-versus-host-disease (GVHD) management procedures
      have significantly reduced the transplant-related mortality (TRM). However, approximately 50%
      of pediatric patients may develop liver dysfunction before HSCT and 74% to 85.5% after HSCT,
      with a TRM related to liver dysfunction reaching 46%. The liver and pancreas complications
      still remain too high for the difficulties and diagnostic inefficiencies and, consequently,
      for the lack of targeted and safer therapies. The diagnostic problems can be summarized in 3
      major points: a) the histological examination of liver and pancreas parenchyma cannot be
      routinely performed because of the organ anatomy and the relative risk of the bioptic
      procedures; b) the lack of specific biomarkers or advanced imaging techniques appropriate for
      the diagnosis of HSCT complications; c) the multifactorial causes of organ complications, as
      well as drug toxicities, GVHD, siderosis, ductopenia (considered as an index of hepatic
      GVHD), the accumulation of potentially toxic substances favored by siderosis and ductopenia.
      In more than 50% of HSCT patients, siderosis and/or ductopenia may represent common
      pathological conditions. Furthermore, international guidelines issued by onco-hematology and
      transplantation scientific societies recommend a chelating treatment with deferasirox in all
      hematological and oncological patients undergoing an intense transfusion regimen. However, in
      the presence of siderosis and marked ductopenia, patients receiving deferasirox may
      experience both severe renal and hematological toxicities and lack of effectiveness of the
      chelating treatment.

      Therefore, the principal aim of the present retrospective study will be the evaluation of the
      transplant-related mortality (TRM) in patients requiring a chelation treatment according to
      the Italian guidelines in pediatric patients
The present retrospective study will be conducted at the Bone Marrow Transplant Center, IRCCS
      Burlo Garofolo, Trieste, Italy. All pediatric patients who underwent one or more allogeneic
      HSCTs between 2010 and 2018 will be enrolled according to inclusion/exclusion criteria.

      The following data will be collected in a retrospective manner:

        -  Data on the underlying disease (diagnosis, therapeutic protocol, transfusion regimen,
           possible relapses, type of transplant, conditioning regimen, infectious complications,
           immunosuppressive treatment, including use of steroids);

        -  Pre-transplant liver and pancreatic function, as well as quantification of iron content
           by nuclear magnetic resonance (MRI);

        -  Pre-transplant histological evaluation of liver parenchyma in case of pre-existing liver
           disease;

        -  Post-transplant liver and pancreatic function and the evaluation of parenchymal
           accumulation of Fe+;

        -  Length and doses of DFX treatment, and corresponding drug plasma concentrations as per
           routine drug monitoring protocols;

        -  Treatment tolerability according to CTC-AE grading V5.0, November 27, 2017 The
           post-transplant data will be collected within 2 years from HSCT (or the last HSCT when
           more than one).

      The data entered in an appropriate anonymous database will be processed by descriptive
      statistics and uni- multivariate statistical analyses according to study endpoints. DFX
      plasma concentrations will be analyzed by means of to a nonlinear mixed effect modeling
      approach to elaborate a population pharmacokinetic (POP/PK) model. POP/PK findings will be
      further analyzed together with clinical and laboratory data.
observational model: Case-Control
time perspective: Retrospective
measure: Transplant-related mortality (TRM)
time frame: 0-24 months after transplant
description: TRM in SIO/SIO+D patients treated with deferasirox as per Italian guidelines
measure: Post-HSCT liver and pancreatic complications
time frame: 0-24 months after transplant
description: Incidence of post-HSCT liver and pancreatic complications in SIO/SIO+D patients treated with deferasirox as per Italian guidelines
measure: Time to iron concentration normalization
time frame: 0-24 months after transplant
description: The times required for the normalization of the Iron Concentration in SIO and SIO+D patients
measure: Statistical analysis of risk factors for ductopenia
time frame: 0-24 months after transplant
description: The correlation between ductopenia and potential risk factors will be investigated by uni- and multi-variate analyses. The following data will be included in the analyses as potential risk factors: chemo-radiotherapy regimens prior to HSCT (drugs and doses), number of blood transfusions
measure: Minimum plasma concentrations of deferasirox
time frame: 0-24 months after transplant
description: In SIO/SIO+D patients, a factorial analysis for mixed data and a nonlinear mixed effect modeling approach will be used to investigate plasma pharmacokinetics of deferasirox in terms of patients' exposure (minimum plasma concentration, Cmin) and to evaluate the effect of identified covariates on drug disposition.
measure: Correlation of minimum plasma concentrations of deferasirox with drug tolerability
time frame: 0-24 months after transplant
description: In SIO/SIO+D patients, uni- and multi-variate analyses will be adopted to assess the correlation of Cmin with treatment tolerability
arm group label: Severe Iron Overload (SIO)
description: Children affected by Severe Iron Overload who received DEFERASIROX
arm group label: Severe Iron Overload + Ductopenia (SIO+D)
description: Children affected by Severe Iron Overload + Ductopenia who received DEFERASIROX
intervention type: Drug
intervention name: Deferasirox
description: DEFERASIROX administered as per clinical practice and according to technical note
arm group label: Severe Iron Overload (SIO)
arm group label: Severe Iron Overload + Ductopenia (SIO+D)
other name: Exjade or Deferasirox Milan
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: 17 Years
healthy volunteers: No
last name: Natalia Maximova, MD
role: Study Director
affiliation: Institute for Maternal and Child Health, IRCCS Burlo Garofalo, Trieste, Italy
facility: 
country: Italy
citation: Oshrine B, Lehmann LE, Duncan CN. Safety and utility of liver biopsy after pediatric hematopoietic stem cell transplantation. J Pediatr Hematol Oncol. 2011 Apr;33(3):e92-7. doi: 10.1097/MPH.0b013e3182025236.
PMID: 21317809
citation: Locasciulli A, Testa M, Valsecchi MG, Vecchi L, Longoni D, Sparano P, Rovelli A, Uderzo C, Masera G, Alberti A. Morbidity and mortality due to liver disease in children undergoing allogeneic bone marrow transplantation: a 10-year prospective study. Blood. 1997 Nov 1;90(9):3799-805.
PMID: 9345068
citation: Quaglia A, Duarte R, Patch D, Ngianga-Bakwin K, Dhillon AP. Histopathology of graft versus host disease of the liver. Histopathology. 2007 May;50(6):727-38. doi: 10.1111/j.1365-2559.2007.02679.x.
PMID: 17493237
citation: Gandon Y, Olivie D, Guyader D, Aube C, Oberti F, Sebille V, Deugnier Y. Non-invasive assessment of hepatic iron stores by MRI. Lancet. 2004 Jan 31;363(9406):357-62. doi: 10.1016/S0140-6736(04)15436-6.
PMID: 15070565
citation: Maximova N, Zanon D, Pascolo L, Zennaro F, Gregori M, Grosso D, Sonzogni A. Metal accumulation in the renal cortex of a pediatric patient with sickle cell disease: a case report and review of the literature. J Pediatr Hematol Oncol. 2015 May;37(4):311-4. doi: 10.1097/MPH.0000000000000322.
PMID: 25811747
responsible party type: Principal Investigator
investigator affiliation: University of Pisa
investigator full name: Antonello Di Paolo, M.D., Ph.D.
investigator title: Associated Professor
mesh term: Iron Overload
mesh term: Deferasirox