<?xml version="1.0" encoding="UTF-8"?>
<clinical_study rank="198">
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  <required_header>
    <download_date>ClinicalTrials.gov processed this data on December 16, 2015</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/show/NCT01615809</url>
  </required_header>
  <id_info>
    <org_study_id>FSJD-ABELNEB-2010</org_study_id>
    <nct_id>NCT01615809</nct_id>
  </id_info>
  <brief_title>Nebulized Amphotericin B Lipid Complex in Invasive Pulmonary Aspergillosis in Paediatric Patients With Acute Leukaemia</brief_title>
  <official_title>A Phase II Trial to Evaluate the Safety and Tolerability of Nebulised Amphotericin B Lipid Complex (ABELCET®) in the Prophylaxis of Invasive Pulmonary Aspergillosis During Prolonged Neutropenia in Paediatric Patients With Acute Leukaemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Fundació Sant Joan de Déu</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Ministry of Health, Spain</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Fundació Sant Joan de Déu</source>
  <oversight_info>
    <authority>Spain: Spanish Agency of Medicines</authority>
    <authority>Spain: Agencia Española de Medicamentos y Productos Sanitarios</authority>
    <authority>Spain: Ministry of Health</authority>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The trial evaluates the overall tolerability of the drug and the efficacy of aerosolised
      amphotericin B as a lipid complex (ABLC) for primary prophylaxis of invasive pulmonary
      aspergillosis (IPA) in pediatric patients with acute leukemia undergoing intensive
      chemotherapy.
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In recent years the incidence of invasive fungal infection (IFI) especially when caused by
      filamentous fungi has increased in patients with haematological malignancies and there
      exists an international consensus on diagnostic criteria. Despite diagnostic and therapeutic
      progress, invasive aspergillosis remains a major clinical problem of haematological
      patients, given the still high mortality rates and the huge economic cost of hospitalization
      of patients, which is attributable to aspergillosis. In addition to the morbidity and
      mortality rates, these infections interfere with the chemotherapy treatment plan with the
      risk of compromising the outcome of the antileukemic treatment.

      In a few uncontrolled studies inhaled amphotericin B deoxycholate showed some benefit in
      haematological patients, however it was not effective in a large multicenter study with
      neutropenic patients. Based on the outcome of that clinical trial, the use of aerosolised
      amphotericin B deoxycholate in neutropenic patients was abandoned for nearly a decade.
      During this time the use of azole agents as drugs of choice for antifungal prophylaxis in
      high risk patients was consolidated. However, one of the main problems in the use of
      triazoles with activity against filamentous fungi (itraconazole, voriconazole, posaconazole)
      is drug-drug interactions due to their CYP3A4 inhibitory activity. One of the most serious
      interactions is that which occurs with vincristine, used throughout the treatment of acute
      lymphoblastic leukemia, and which has lead to reports of neurotoxicity due to metabolic
      inhibition.

      ABLC (Abelcet®) belongs to the group of polyenes with antifungal activity against a broad
      spectrum of fungal species, including Aspergillus spp. The active component of ABELCET®,
      amphotericin B, acts by binding to sterols in the cell membrane of susceptible fungi, with a
      resultant change in the permeability of the membrane. Mammalian cell membranes also contain
      sterols, and damage to human cells is believed to occur through the same mechanism of
      action.

      Abelcet® is recommended for the intravenous treatment of a broad spectrum of systemic fungal
      infections in adult patients. Although it has a pediatric indication, there are numerous
      studies published regarding the safety levels of Abelcet® administered intravenously in
      children and in haematological adults patients which look very promising. In this context,
      the working hypothesis proposed in this project is that the administration of aerosolised
      ABLC for pediatric patients with acute leukemia treated with intensive chemotherapy will be
      an effective alternative as a prophylaxis of pulmonary fungal infections in these patients.

      In the treatment of pediatric patients with haematological malignancies the use of intensive
      chemotherapy is required, which is immunosuppressive and therefore significantly increases
      the risk of IFI, especially filamentous fungi. IPA is associated with high mortality (&gt;50%)
      in those patients, making it imperative to adopt effective, preventive, prophylactic
      measures. Drug interactions occur frequently with triazole antifungal drugs; cases of
      clinically significant interactions with vincristine, an anchor drug in the treatment of the
      majority of pediatric leukemia, are documented. On the other hand, there are promising data
      from previous studies regarding the safety and efficacy of the intravenous ABLC formulation
      (Abelcet®) in the treatment of pediatric patients with fungal infections.

      If the working hypothesis is confirmed, the aerosolised ABLC treatment would be an
      effective, safe and reliable prophylactic option for IPA. It would offer an alternative to
      the systemic administration of antifungal triazoles without affecting the antileukemic
      treatment in pediatric patients with AL.
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2011</start_date>
  <completion_date type="Actual">July 2013</completion_date>
  <primary_completion_date type="Actual">July 2013</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <study_design>Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment</study_design>
  <primary_outcome>
    <measure>Number of Participants With Adverse Events That Results in the Interruption of Treatment, as a Measure of Safety and Tolerability</measure>
    <time_frame>at the Baseline visit (week 1) and during the Last week of treatment, up to 6 weeks</time_frame>
    <safety_issue>Yes</safety_issue>
    <description>is assessed by the proportion of patients who discontinue prophylactic treatment with Abelcet® due to an adverse event that is related or not to the study drug or for intolerability to it. The last week of treatment will have a different calendar for each participant, depending on the number of cicles needed by each patient (it has been anticipated up to 5 cicles of 2-6 weeks each).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Efficacy of Primary Prophylaxis With Nebulized Abelcet® on the Incidence of Invasive Pulmonary Aspergillosis (IPA) in Paediatric Patients With Acute Leukaemia (AL) Undergoing Intensive Chemotherapy</measure>
    <time_frame>at the Baseline visit (week 1) and at the end of the profilaxis treatment phase, up to 6 weeks</time_frame>
    <safety_issue>No</safety_issue>
    <description>The Incidence of IPA during the Abelcet® prophylactic treatment period was assessed by the relation between the number of patients with IPA and the number of patients on prophylaxis.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Invasive Pulmonary Aspergillosis (IPA)-Related Mortality During Primary Prophylaxis With Abelcet® in Paediatric Patients With (AL) Undergoing Intensive Chemotherapy.</measure>
    <time_frame>at the Baseline visit (week 1) and at the end of the profilaxis treatment phase, up to 6 weeks</time_frame>
    <safety_issue>Yes</safety_issue>
    <description>Percentage of deaths related to API during the prophylactic treatment period with Abelcet® in paediatric patients with (AL) undergoing intensive chemotherapy</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">32</enrollment>
  <condition>Invasive Pulmonary Aspergillosis</condition>
  <condition>Lymphoblastic Leukaemia</condition>
  <condition>Myeloblastic Leukaemia</condition>
  <condition>Lymphoblastic Leukemia</condition>
  <condition>Myeloblastic Leukemia</condition>
  <arm_group>
    <arm_group_label>Amphotericin B (ABELCET®)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients fulfilling inclusion criteria and those giving the general informed consent for the study will initiate nebulized Amphotericin B prophylaxis treatment, twice a week, during neutropenia periods (coincident with intensive chemotherapy treatment).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AMPHOTERICIN B</intervention_name>
    <description>The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.The administration regimen for each Abelcet® nebulization will be 10 ml (50 mg) twice a week for the first week, and then from the second week onwards it will be 5 ml (25 mg) with a minimum separation of 72 hours between doses, until the neutrophil count is greater than or equal to 1500 cells/mm3.</description>
    <arm_group_label>Amphotericin B (ABELCET®)</arm_group_label>
    <other_name>Abelcet® 5 mg/ml</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:

          1. Age: patients between 3 and 18 years.

          2. Diagnosis of myeloblastic or lymphoblastic AL during intensive chemotherapy.

          3. Informed consent of parents/guardians and/or assent of the patient has been obtained.

        Exclusion Criteria:

          1. Probable or proven invasive pulmonary fungal infection before entering the trial.

          2. Previous chronic renal impairment or baseline serum creatinine &gt; 2.5 mg /dL

          3. Severe hepatic impairment.

          4. Moderate-severe asthma being treated pharmacologically.

          5. Antifungal treatment for filamentous fungi in the last 4 weeks.

          6. Participating or have participated in a clinical trial during the last 4 weeks.

          7. Mentally retarded

          8. Known allergy or hypersensitivity to the active ingredient of the study drug or to
             any of its excipients.

          9. Any serious concomitant disease that in the investigator's opinion could compromise
             the completion of the trial or affect the patient's tolerability to this treatment.

         10. Pregnancy (in women of fertile age).

         11. Breast-feeding.

        Patients are defined as having probable IFI when their radiological image is suggestive of
        fungal infection and they have positive antigenemia for Aspergillus. IFI would be proven
        when the presence of Aspergillus is confirmed in aspirate culture or by lung biopsy.
      </textblock>
    </criteria>
    <gender>Both</gender>
    <minimum_age>3 Years</minimum_age>
    <maximum_age>17 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jesus Estella, PhMD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hospital Sant Joan de Deu</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hospital Sant Joan de Déu</name>
      <address>
        <city>Esplugues de Llobregat</city>
        <state>Barcelona</state>
        <zip>08950</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Spain</country>
  </location_countries>
  <link>
    <url>http://www.hsjdbcn.org</url>
    <description>Sponsor's Website</description>
  </link>
  <reference>
    <citation>Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, Donnelly JP, Edwards JE, Erjavec Z, Fiere D, Lortholary O, Maertens J, Meis JF, Patterson TF, Ritter J, Selleslag D, Shah PM, Stevens DA, Walsh TJ; Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer; Mycoses Study Group of the National Institute of Allergy and Infectious Diseases. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis. 2002 Jan 1;34(1):7-14. Epub 2001 Nov 26.</citation>
    <PMID>11731939</PMID>
  </reference>
  <reference>
    <citation>Walsh TJ, Gonzalez C, Lyman CA, Chanock SJ, Pizzo PA. Invasive fungal infections in children: recent advances in diagnosis and treatment. Adv Pediatr Infect Dis. 1996;11:187-290. Review.</citation>
    <PMID>8718464</PMID>
  </reference>
  <reference>
    <citation>Blyth CC, Palasanthiran P, O'Brien TA. Antifungal therapy in children with invasive fungal infections: a systematic review. Pediatrics. 2007 Apr;119(4):772-84. Review.</citation>
    <PMID>17403849</PMID>
  </reference>
  <reference>
    <citation>Bodey GP, Anaissie EJ, Elting LS, Estey E, O'Brien S, Kantarjian H. Antifungal prophylaxis during remission induction therapy for acute leukemia fluconazole versus intravenous amphotericin B. Cancer. 1994 Apr 15;73(8):2099-106.</citation>
    <PMID>8156515</PMID>
  </reference>
  <reference>
    <citation>Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systematic review of the literature. Clin Infect Dis. 2001 Feb 1;32(3):358-66. Epub 2001 Jan 26. Review.</citation>
    <PMID>11170942</PMID>
  </reference>
  <reference>
    <citation>Perfect JR, Klotman ME, Gilbert CC, Crawford DD, Rosner GL, Wright KA, Peters WP. Prophylactic intravenous amphotericin B in neutropenic autologous bone marrow transplant recipients. J Infect Dis. 1992 May;165(5):891-7.</citation>
    <PMID>1569339</PMID>
  </reference>
  <reference>
    <citation>Walsh TJ, Hiemenz J, Pizzo PA. Evolving risk factors for invasive fungal infections--all neutropenic patients are not the same. Clin Infect Dis. 1994 May;18(5):793-8.</citation>
    <PMID>8075273</PMID>
  </reference>
  <reference>
    <citation>Walsh TJ, Hiemenz JW, Anaissie E. Recent progress and current problems in treatment of invasive fungal infections in neutropenic patients. Infect Dis Clin North Am. 1996 Jun;10(2):365-400. Review.</citation>
    <PMID>8803625</PMID>
  </reference>
  <reference>
    <citation>Walsh TJ, Finberg RW, Arndt C, Hiemenz J, Schwartz C, Bodensteiner D, Pappas P, Seibel N, Greenberg RN, Dummer S, Schuster M, Holcenberg JS. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med. 1999 Mar 11;340(10):764-71.</citation>
    <PMID>10072411</PMID>
  </reference>
  <reference>
    <citation>Herbrecht R. The changing epidemiology of fungal infections: are the lipid-forms of amphotericin B an advance? Eur J Haematol Suppl. 1996;57:12-7. Review.</citation>
    <PMID>8706811</PMID>
  </reference>
  <reference>
    <citation>Herbrecht R. Improving the outcome of invasive aspergillosis: new diagnostic tools and new therapeutic strategies. Ann Hematol. 2002;81 Suppl 2:S52-3.</citation>
    <PMID>12611078</PMID>
  </reference>
  <reference>
    <citation>Nakagawa Y. [Prophylactic administration of fluconazole and itraconazole in febrile neutropenia associated with hematopoietic malignancy]. Jpn J Antibiot. 2006 Oct;59(5):407-9. Japanese.</citation>
    <PMID>17205660</PMID>
  </reference>
  <reference>
    <citation>Boettcher H, Bewig B, Hirt SW, Möller F, Cremer J. Topical amphotericin B application in severe bronchial aspergillosis after lung transplantation: report of experiences in 3 cases. J Heart Lung Transplant. 2000 Dec;19(12):1224-7.</citation>
    <PMID>11124494</PMID>
  </reference>
  <reference>
    <citation>Alexander BD, Dodds Ashley ES, Addison RM, Alspaugh JA, Chao NJ, Perfect JR. Non-comparative evaluation of the safety of aerosolized amphotericin B lipid complex in patients undergoing allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis. 2006 Mar;8(1):13-20.</citation>
    <PMID>16623816</PMID>
  </reference>
  <reference>
    <citation>Rijnders BJ, Cornelissen JJ, Slobbe L, Becker MJ, Doorduijn JK, Hop WC, Ruijgrok EJ, Löwenberg B, Vulto A, Lugtenburg PJ, de Marie S. Aerosolized liposomal amphotericin B for the prevention of invasive pulmonary aspergillosis during prolonged neutropenia: a randomized, placebo-controlled trial. Clin Infect Dis. 2008 May 1;46(9):1401-8. doi: 10.1086/586739.</citation>
    <PMID>18419443</PMID>
  </reference>
  <verification_date>November 2015</verification_date>
  <lastchanged_date>November 4, 2015</lastchanged_date>
  <firstreceived_date>June 4, 2012</firstreceived_date>
  <firstreceived_results_date>August 28, 2015</firstreceived_results_date>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Invasive pulmonary aspergillosis</keyword>
  <keyword>IFI</keyword>
  <keyword>Leukaemia</keyword>
  <keyword>Leukemia</keyword>
  <keyword>Pediatric</keyword>
  <keyword>Paediatrics</keyword>
  <keyword>Amphotericin B</keyword>
  <keyword>Aspergillosis</keyword>
  <keyword>Pulmonary Aspergillosis</keyword>
  <keyword>Invasive Aspergillosis</keyword>
  <keyword>Antifungal agents</keyword>
  <keyword>Fungal infections</keyword>
  <keyword>Invasive Fungal Infection</keyword>
  <is_fda_regulated>No</is_fda_regulated>
  <has_expanded_access>No</has_expanded_access>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm  -->
    <mesh_term>Aspergillosis</mesh_term>
    <mesh_term>Invasive Pulmonary Aspergillosis</mesh_term>
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Precursor Cell Lymphoblastic Leukemia-Lymphoma</mesh_term>
    <mesh_term>Pulmonary Aspergillosis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm  -->
    <mesh_term>Amphotericin B</mesh_term>
    <mesh_term>Liposomal amphotericin B</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Amphotericin B (ABELCET®)</title>
          <description>Patients fulfilling inclusion criteria and those giving the general informed consent for the study will initiate nebulized Amphotericin B prophylaxis treatment, twice a week, during neutropenia periods (coincident with intensive chemotherapy treatment).
AMPHOTERICIN B: The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.The administration regimen for each Abelcet® nebulization will be 10 ml (50 mg) twice a week for the first week, and then from the second week onwards it will be 5 ml (25 mg) with a minimum separation of 72 hours between doses, until the neutrophil count is greater than or equal to 1500 cells/mm3.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="32">basal visit</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>pediatric patients</population>
      <group_list>
        <group group_id="B1">
          <title>Amphotericin B (ABELCET®)</title>
          <description>Patients fulfilling inclusion criteria and those giving the general informed consent for the study initiate nebulized Amphotericin B prophylaxis treatment, twice a week, during neutropenia periods (coincident with intensive chemotherapy treatment).
AMPHOTERICIN B: The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.The administration regimen for each Abelcet® nebulization was 10 ml (50 mg) twice a week for the first week, and then from the second week onwards was reduced to 5 ml (25 mg) with a minimum separation of 72 hours between doses, until the neutrophil count demonstrated to be greater than or equal to 1500 cells/mm3.</description>
        </group>
      </group_list>
      <measure_list>
        <measure>
          <title>Number of Participants</title>
          <units>participants</units>
          <param>Number</param>
          <category_list>
            <category>
              <measurement_list>
                <measurement group_id="B1" value="32"/>
              </measurement_list>
            </category>
          </category_list>
        </measure>
        <measure>
          <title>Age, Customized</title>
          <units>participants</units>
          <param>Number</param>
          <category_list>
            <category>
              <sub_title>&gt;= 3 years to &lt;=18 years</sub_title>
              <measurement_list>
                <measurement group_id="B1" value="32"/>
              </measurement_list>
            </category>
          </category_list>
        </measure>
        <measure>
          <title>Gender</title>
          <units>participants</units>
          <param>Number</param>
          <category_list>
            <category>
              <sub_title>Female</sub_title>
              <measurement_list>
                <measurement group_id="B1" value="13"/>
              </measurement_list>
            </category>
            <category>
              <sub_title>Male</sub_title>
              <measurement_list>
                <measurement group_id="B1" value="19"/>
              </measurement_list>
            </category>
          </category_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <description>patients ethnicity percentage : caucasian (84.4%), Amerindian (6.3%), African (3.1%) and gypsies (6.3%).</description>
          <units>participants</units>
          <param>Number</param>
          <category_list>
            <category>
              <sub_title>caucasian</sub_title>
              <measurement_list>
                <measurement group_id="B1" value="27"/>
              </measurement_list>
            </category>
            <category>
              <sub_title>amerindian</sub_title>
              <measurement_list>
                <measurement group_id="B1" value="2"/>
              </measurement_list>
            </category>
            <category>
              <sub_title>african</sub_title>
              <measurement_list>
                <measurement group_id="B1" value="1"/>
              </measurement_list>
            </category>
            <category>
              <sub_title>gypsies</sub_title>
              <measurement_list>
                <measurement group_id="B1" value="2"/>
              </measurement_list>
            </category>
          </category_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>center</units>
          <param>Number</param>
          <category_list>
            <category>
              <sub_title>Spain</sub_title>
              <measurement_list>
                <measurement group_id="B1" value="32"/>
              </measurement_list>
            </category>
          </category_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Adverse Events That Results in the Interruption of Treatment, as a Measure of Safety and Tolerability</title>
        <description>is assessed by the proportion of patients who discontinue prophylactic treatment with Abelcet® due to an adverse event that is related or not to the study drug or for intolerability to it. The last week of treatment will have a different calendar for each participant, depending on the number of cicles needed by each patient (it has been anticipated up to 5 cicles of 2-6 weeks each).</description>
        <time_frame>at the Baseline visit (week 1) and during the Last week of treatment, up to 6 weeks</time_frame>
        <safety_issue>Yes</safety_issue>
        <population>pediatric patients</population>
        <group_list>
          <group group_id="O1">
            <title>Amphotericin B (ABELCET®)</title>
            <description>Patients fulfilling inclusion criteria and those giving the general informed consent for the study will initiate nebulized Amphotericin B prophylaxis treatment, twice a week, during neutropenia periods (coincident with intensive chemotherapy treatment).
AMPHOTERICIN B: The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.The administration regimen for each Abelcet® nebulization will be 10 ml (50 mg) twice a week for the first week, and then from the second week onwards it will be 5 ml (25 mg) with a minimum separation of 72 hours between doses, until the neutrophil count is greater than or equal to 1500 cells/mm3.</description>
          </group>
        </group_list>
        <measure_list>
          <measure>
            <title>Number of Participants</title>
            <units>participants</units>
            <param>Number</param>
            <category_list>
              <category>
                <measurement_list>
                  <measurement group_id="O1" value="32"/>
                </measurement_list>
              </category>
            </category_list>
          </measure>
          <measure>
            <title>Number of Participants With Adverse Events That Results in the Interruption of Treatment, as a Measure of Safety and Tolerability</title>
            <description>is assessed by the proportion of patients who discontinue prophylactic treatment with Abelcet® due to an adverse event that is related or not to the study drug or for intolerability to it. The last week of treatment will have a different calendar for each participant, depending on the number of cicles needed by each patient (it has been anticipated up to 5 cicles of 2-6 weeks each).</description>
            <units>participants</units>
            <param>Number</param>
            <category_list>
              <category>
                <measurement_list>
                  <measurement group_id="O1" value="0"/>
                </measurement_list>
              </category>
            </category_list>
          </measure>
        </measure_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Efficacy of Primary Prophylaxis With Nebulized Abelcet® on the Incidence of Invasive Pulmonary Aspergillosis (IPA) in Paediatric Patients With Acute Leukaemia (AL) Undergoing Intensive Chemotherapy</title>
        <description>The Incidence of IPA during the Abelcet® prophylactic treatment period was assessed by the relation between the number of patients with IPA and the number of patients on prophylaxis.</description>
        <time_frame>at the Baseline visit (week 1) and at the end of the profilaxis treatment phase, up to 6 weeks</time_frame>
        <safety_issue>No</safety_issue>
        <population>At baseline, none of the 32 pediatric patients with acute leukemia included in the clinical trial had API. During the trial period there were 3 patients who developed API</population>
        <group_list>
          <group group_id="O1">
            <title>Amphotericin B (ABELCET®)</title>
            <description>Patients fulfilling inclusion criteria and those giving the general informed consent for the study will initiate nebulized Amphotericin B prophylaxis treatment, twice a week, during neutropenia periods (coincident with intensive chemotherapy treatment).
AMPHOTERICIN B: The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.The administration regimen for each Abelcet® nebulization will be 10 ml (50 mg) twice a week for the first week, and then from the second week onwards it will be 5 ml (25 mg) with a minimum separation of 72 hours between doses, until the neutrophil count is greater than or equal to 1500 cells/mm3.</description>
          </group>
        </group_list>
        <measure_list>
          <measure>
            <title>Number of Participants</title>
            <units>participants</units>
            <param>Number</param>
            <category_list>
              <category>
                <measurement_list>
                  <measurement group_id="O1" value="32"/>
                </measurement_list>
              </category>
            </category_list>
          </measure>
          <measure>
            <title>Efficacy of Primary Prophylaxis With Nebulized Abelcet® on the Incidence of Invasive Pulmonary Aspergillosis (IPA) in Paediatric Patients With Acute Leukaemia (AL) Undergoing Intensive Chemotherapy</title>
            <description>The Incidence of IPA during the Abelcet® prophylactic treatment period was assessed by the relation between the number of patients with IPA and the number of patients on prophylaxis.</description>
            <units>participants</units>
            <param>Number</param>
            <category_list>
              <category>
                <measurement_list>
                  <measurement group_id="O1" value="3"/>
                </measurement_list>
              </category>
            </category_list>
          </measure>
        </measure_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Invasive Pulmonary Aspergillosis (IPA)-Related Mortality During Primary Prophylaxis With Abelcet® in Paediatric Patients With (AL) Undergoing Intensive Chemotherapy.</title>
        <description>Percentage of deaths related to API during the prophylactic treatment period with Abelcet® in paediatric patients with (AL) undergoing intensive chemotherapy</description>
        <time_frame>at the Baseline visit (week 1) and at the end of the profilaxis treatment phase, up to 6 weeks</time_frame>
        <safety_issue>Yes</safety_issue>
        <group_list>
          <group group_id="O1">
            <title>Amphotericin B (ABELCET®)</title>
            <description>Patients fulfilling inclusion criteria and those giving the general informed consent for the study will initiate nebulized Amphotericin B prophylaxis treatment, twice a week, during neutropenia periods (coincident with intensive chemotherapy treatment).
AMPHOTERICIN B: The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.The administration regimen for each Abelcet® nebulization will be 10 ml (50 mg) twice a week for the first week, and then from the second week onwards it will be 5 ml (25 mg) with a minimum separation of 72 hours between doses, until the neutrophil count is greater than or equal to 1500 cells/mm3.</description>
          </group>
        </group_list>
        <measure_list>
          <measure>
            <title>Number of Participants</title>
            <units>participants</units>
            <param>Number</param>
            <category_list>
              <category>
                <measurement_list>
                  <measurement group_id="O1" value="32"/>
                </measurement_list>
              </category>
            </category_list>
          </measure>
          <measure>
            <title>Invasive Pulmonary Aspergillosis (IPA)-Related Mortality During Primary Prophylaxis With Abelcet® in Paediatric Patients With (AL) Undergoing Intensive Chemotherapy.</title>
            <description>Percentage of deaths related to API during the prophylactic treatment period with Abelcet® in paediatric patients with (AL) undergoing intensive chemotherapy</description>
            <units>percentage of deaths</units>
            <param>Number</param>
            <dispersion>95% Confidence Interval</dispersion>
            <category_list>
              <category>
                <measurement_list>
                  <measurement group_id="O1" value="0" lower_limit="0" upper_limit="0"/>
                </measurement_list>
              </category>
            </category_list>
          </measure>
        </measure_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Amphotericin B (ABELCET®)</title>
          <description>Patients fulfilling inclusion criteria and those giving the general informed consent for the study will initiate nebulized Amphotericin B prophylaxis treatment, twice a week, during neutropenia periods (coincident with intensive chemotherapy treatment).
AMPHOTERICIN B: The study drug will be administered by inhalation, to hospitalised patients or outpatients in the day hospital.The administration regimen for each Abelcet® nebulization will be 10 ml (50 mg) twice a week for the first week, and then from the second week onwards it will be 5 ml (25 mg) with a minimum separation of 72 hours between doses, until the neutrophil count is greater than or equal to 1500 cells/mm3.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="22" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>febrile neutropenia</sub_title>
                <counts group_id="E1" events="26" subjects_affected="16" subjects_at_risk="32"/>
              </event>
              <event>
                <sub_title>Febrile Aplasia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="32"/>
              </event>
              <event>
                <sub_title>macroscopic hematuria</sub_title>
                <counts group_id="E1" events="3" subjects_affected="1" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>fever</sub_title>
                <counts group_id="E1" events="13" subjects_affected="8" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>hyperglycemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Methotrexate-induced neurotoxicity</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="32" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>abdominal pain</sub_title>
                <counts group_id="E1" events="32" subjects_affected="29" subjects_at_risk="32"/>
              </event>
              <event>
                <sub_title>diarrhea</sub_title>
                <counts group_id="E1" events="32" subjects_affected="21" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="32" subjects_affected="32" subjects_at_risk="32"/>
              </event>
              <event>
                <sub_title>paleness</sub_title>
                <counts group_id="E1" events="32" subjects_affected="28" subjects_at_risk="32"/>
              </event>
              <event>
                <sub_title>physical pain</sub_title>
                <counts group_id="E1" events="32" subjects_affected="24" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Rosa Maria morales Palau</name_or_title>
      <organization>Fundaciò per la Recerca i la Docencia sant Joan de Deu</organization>
      <phone>936009751</phone>
      <email>rmorales@fsjd.org</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>
