<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/NCT02981615</url>
  </required_header>
  <id_info>
    <org_study_id>1680-14-SMC</org_study_id>
    <nct_id>NCT02981615</nct_id>
  </id_info>
  <brief_title>Phase 3 Multicenter Randomized Double Blind Placebo Controlled Study With Antibacterial Prophylaxis in Azacitidine Treated MDS Patients</brief_title>
  <official_title>A Phase 3, Multicenter, Randomized, Double Blind, Placebo Controlled Study to Assess the Safety and Efficacy of Antibacterial Prophylaxis for Prevention of Infections in Azacitidine Treated Myelodysplastic Syndrome Patients.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sheba Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Sheba Medical Center</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>
      Infections are a major and prevalent life-threatening complication among patients with&#xD;
      myelodysplastic syndrome (MDS). Currently, the role of prophylactic antibacterial agents&#xD;
      after chemotherapy in MDS patients remains controversial and there are no clinical guidelines&#xD;
      for infection prophylaxis in this clinical setting. We will conduct a prospective study to&#xD;
      evaluate the potential benefit of prophylactic antibacterial (Levofloxacin) on the rate of&#xD;
      febrile episodes/infections in Azacytidine treated MDS patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a national, multicenter, phase III, randomized, parallel arms, double blind, placebo&#xD;
      controlled clinical trial to evaluate the efficacy and safety of antibacterial prophylaxis -&#xD;
      Levofloxacin 500mg/d given p.o.in newly diagnosed MDS patients who are more than 18 years of&#xD;
      age and fulfil an indication for Azacytidine treatment. Patients will be treated for up to 4&#xD;
      cycles of Levofloxacin, or placebo. Subjects allocated to the treatment arm of the study will&#xD;
      be administrated Levofloxacin 500mg/d given p.o. once a day, starting on day 10 from&#xD;
      beginning of each cycle until day 28. Subject allocated to the placebo arm will be treated&#xD;
      with placebo once a day, starting on day 10 from beginning of each cycle until day 28.&#xD;
      Levofloxacin and placebo treatment will be continued in the first 4 Azacytidine cycles. This&#xD;
      study consists of 3 periods for each study subject: pre-treatment period, treatment period&#xD;
      and follow up period. Expected duration of subject participation is 6 months Pre-treatment&#xD;
      period: Assessments: MDS evaluation by bone marrow examination including cytogenetics/ FISH&#xD;
      must be performed within half a year of the first dose of study drug.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">August 1, 2017</start_date>
  <completion_date type="Anticipated">December 2019</completion_date>
  <primary_completion_date type="Anticipated">December 2019</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Febrile episodes (fever &gt;38.0c) rate.</measure>
    <time_frame>from study entry to 6 months later</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to first febrile episode</measure>
    <time_frame>from study entry to 6 months later</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinically-documented (CDI) or microbiologically documented infections rate (MDI)</measure>
    <time_frame>from study entry to 6 months later</time_frame>
    <description>Clinically-documented (CDI) or microbiologically documented infections (MDI) other than bacteremia, defined as sepsis inflammatory response syndrome (SIRS) associated with local inflammation (e.g. pneumonia, UTI, abdominal infection) with or without microbiological documentation from the site of infection, excluding episodes accompanied by bacteremia. Virologically documented infections will not be included as MDIs</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Bacteremia rate</measure>
    <time_frame>from study entry to 6 months later</time_frame>
    <description>Bacteremia, defined SIRS accompanied by growth of a bloodstream isolate in one or more blood culture. Growth of typical skin commensals (coagulase-negative Staphylococci, diphtheroids) will require growth from at least two separate sets of blood cultures.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Invasive fungal infections rate, as defined by the EORTC/MSG consensus group</measure>
    <time_frame>from study entry to 6 months later</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of participants use of antibacterial therapy other than levofloxain prophylaxis.</measure>
    <time_frame>from study entry to 6 months later</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Episodes of diarrhea rate</measure>
    <time_frame>from study entry to 6 months later</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>C. difficile infection rate</measure>
    <time_frame>from study entry to 6 months later</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>MDIs or bacteremia caused by quinolone-resistant bacteria rate</measure>
    <time_frame>from study entry to 6 months later</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hospitalization for infection rate.</measure>
    <time_frame>from study entry to 6 months later</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Six months overall survival rate.</measure>
    <time_frame>from study entry to 6 months later</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>QOL as measured by the FACT An questioner.</measure>
    <time_frame>from study entry to 6 months later</time_frame>
  </secondary_outcome>
  <other_outcome>
    <measure>Correlation between serum ferritin level (&gt; 1000ng/ml) as a predictor of the infection rate</measure>
    <time_frame>from study entry to 4months later</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Correlation between serum ferritin level (&gt; 1000ng/ml) as a predictor of mortality rate</measure>
    <time_frame>from study entry to 6 months later</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Correlation of antibiotic prophylaxis use versus placebo on the rate of infections</measure>
    <time_frame>from study entry to 6 months later</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Correlation of antibiotic prophylaxis use versus placebo on the mortality rate</measure>
    <time_frame>from study entry to 6 months later</time_frame>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">170</enrollment>
  <condition>Prevention</condition>
  <arm_group>
    <arm_group_label>treatment arm</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects allocated to the treatment arm of the study will be administrated Levofloxacin 500mg/d given p.o. once a day, starting on day 10 from beginning of each cycle until day 28 on an ambulatory basis. Levofloxacin will be continued in the first 4 Azacytidine cycles.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subject allocated to the placebo arm will be treated with placebo once a day, starting on day 10 from beginning until day 28 of each of the first 4 cycles.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Levofloxacin</intervention_name>
    <description>one tablet (500mg) a day, from day 10 to day 28 in every cycle of the 4 first cycles</description>
    <arm_group_label>treatment arm</arm_group_label>
    <other_name>levo, tavanic</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Tablet</intervention_name>
    <description>one tablet a day, from day 10 to day 28 in every cycle of the 4 first cycles</description>
    <arm_group_label>placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Age &gt; 18 years at the time of signing the informed consent document.&#xD;
&#xD;
          2. Have a documented diagnosis of primary or secondary MDS according to WHO 2008&#xD;
             classification (appendix I), fulfilling an indication for Azacytidine treatment.&#xD;
&#xD;
          3. Females of childbearing potential (FCBP) may participate, providing they meet the&#xD;
             following conditions: Agree to use at least two effective contraceptive methods (oral,&#xD;
             injectable, or implantable hormonal contraceptive; tubal ligation; intra uterine&#xD;
             device; barrier contraceptive with spermicide; or vasectomized partner) throughout the&#xD;
             study, and for 3 months following the last dose of study drug; and have a negative&#xD;
             serum or urine pregnancy test (investigator's discretion; sensitivity at least 25&#xD;
             mIU/mL) at screening; and have a negative serum or urine pregnancy test&#xD;
             (investigator's discretion) within 72 hours prior to starting study therapy in the&#xD;
             treatment phase (note that the screening serum pregnancy test can be used as the test&#xD;
             prior to starting study therapy in treatment phase if it is performed within the&#xD;
             72-hour time frame).&#xD;
&#xD;
          4. Male subjects with a female partner of childbearing potential must agree to the use of&#xD;
             at least two physician-approved contraceptive methods throughout the course of the&#xD;
             study and should avoid fathering a child during the course of the study and for 3&#xD;
             months following the last dose of study drug.&#xD;
&#xD;
          5. Understand and voluntarily sign an informed consent document prior to any study&#xD;
             related assessments/procedures being conducted.&#xD;
&#xD;
          6. Able to adhere to the study visit schedule and other protocol requirements.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Prior treatment with any of the following:&#xD;
&#xD;
        1.1. Azacitidine (any formulation), decitabine or other hypomethylating agent 1.2.&#xD;
        Lenalidomide 2. Prior allogeneic or autologous stem cell transplant 3. Use of hydroxyurea&#xD;
        within 7 days prior to randomization. 4. Diagnosis of AML (i.e. &gt;30% blasts in bone&#xD;
        marrow). 5. Ongoing adverse events from previous treatment, regardless of the time period.&#xD;
        6. Systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms&#xD;
        related to the infection without improvement despite appropriate antibiotics, antiviral&#xD;
        therapy, and/or other treatment) 7. Known Human Immunodeficiency Virus (HIV) 8. Known or&#xD;
        suspected hypersensitivity to azacitidine or mannitol. 9. Known or suspected&#xD;
        hypersensitivity to Levofloxacin. 10. Pregnant or lactating females. 11. Any significant&#xD;
        medical condition, laboratory abnormality, or psychiatric illness that would prevent the&#xD;
        subject from participating in the study. 12. Any condition including the presence of&#xD;
        laboratory abnormalities, which places the subject at unacceptable risk if he/she were to&#xD;
        participate in the study. 13. Participation to an investigational drug trial in the last&#xD;
        month before randomization.&#xD;
&#xD;
        -&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Drorit G Merkel, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sheba Medical Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Drorit G Merkel, MD</last_name>
    <phone>972526669168</phone>
    <email>drorit.merkel@sheba.health.gov.il</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Yshai Ofran, MD</last_name>
    <phone>972-50-2061524</phone>
    <email>y_ofran@rambam.health.gov.il</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Chim Sheba Medical Center</name>
      <address>
        <city>Tel Hashomer</city>
        <zip>52621</zip>
        <country>Israel</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Merkel Drorit, MD</last_name>
      <phone>972526669168</phone>
      <email>drorit.merkel@sheba.health.gov.il</email>
    </contact>
  </location>
  <location_countries>
    <country>Israel</country>
  </location_countries>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>November 28, 2016</study_first_submitted>
  <study_first_submitted_qc>November 30, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 5, 2016</study_first_posted>
  <last_update_submitted>January 25, 2018</last_update_submitted>
  <last_update_submitted_qc>January 25, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">January 26, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Sheba Medical Center</investigator_affiliation>
    <investigator_full_name>Dr. Drorit Merkel</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Levofloxacin</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/NCT02981615
org study id: 1680-14-SMC
nct id: NCT02981615
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Infections are a major and prevalent life-threatening complication among patients with
      myelodysplastic syndrome (MDS). Currently, the role of prophylactic antibacterial agents
      after chemotherapy in MDS patients remains controversial and there are no clinical guidelines
      for infection prophylaxis in this clinical setting. We will conduct a prospective study to
      evaluate the potential benefit of prophylactic antibacterial (Levofloxacin) on the rate of
      febrile episodes/infections in Azacytidine treated MDS patients.
This is a national, multicenter, phase III, randomized, parallel arms, double blind, placebo
      controlled clinical trial to evaluate the efficacy and safety of antibacterial prophylaxis -
      Levofloxacin 500mg/d given p.o.in newly diagnosed MDS patients who are more than 18 years of
      age and fulfil an indication for Azacytidine treatment. Patients will be treated for up to 4
      cycles of Levofloxacin, or placebo. Subjects allocated to the treatment arm of the study will
      be administrated Levofloxacin 500mg/d given p.o. once a day, starting on day 10 from
      beginning of each cycle until day 28. Subject allocated to the placebo arm will be treated
      with placebo once a day, starting on day 10 from beginning of each cycle until day 28.
      Levofloxacin and placebo treatment will be continued in the first 4 Azacytidine cycles. This
      study consists of 3 periods for each study subject: pre-treatment period, treatment period
      and follow up period. Expected duration of subject participation is 6 months Pre-treatment
      period: Assessments: MDS evaluation by bone marrow examination including cytogenetics/ FISH
      must be performed within half a year of the first dose of study drug.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Double (Participant, Investigator)
measure: Febrile episodes (fever >38.0c) rate.
time frame: from study entry to 6 months later
measure: Time to first febrile episode
time frame: from study entry to 6 months later
measure: Clinically-documented (CDI) or microbiologically documented infections rate (MDI)
time frame: from study entry to 6 months later
description: Clinically-documented (CDI) or microbiologically documented infections (MDI) other than bacteremia, defined as sepsis inflammatory response syndrome (SIRS) associated with local inflammation (e.g. pneumonia, UTI, abdominal infection) with or without microbiological documentation from the site of infection, excluding episodes accompanied by bacteremia. Virologically documented infections will not be included as MDIs
measure: Bacteremia rate
time frame: from study entry to 6 months later
description: Bacteremia, defined SIRS accompanied by growth of a bloodstream isolate in one or more blood culture. Growth of typical skin commensals (coagulase-negative Staphylococci, diphtheroids) will require growth from at least two separate sets of blood cultures.
measure: Invasive fungal infections rate, as defined by the EORTC/MSG consensus group
time frame: from study entry to 6 months later
measure: Number of participants use of antibacterial therapy other than levofloxain prophylaxis.
time frame: from study entry to 6 months later
measure: Episodes of diarrhea rate
time frame: from study entry to 6 months later
measure: C. difficile infection rate
time frame: from study entry to 6 months later
measure: MDIs or bacteremia caused by quinolone-resistant bacteria rate
time frame: from study entry to 6 months later
measure: Hospitalization for infection rate.
time frame: from study entry to 6 months later
measure: Six months overall survival rate.
time frame: from study entry to 6 months later
measure: QOL as measured by the FACT An questioner.
time frame: from study entry to 6 months later
measure: Correlation between serum ferritin level (> 1000ng/ml) as a predictor of the infection rate
time frame: from study entry to 4months later
measure: Correlation between serum ferritin level (> 1000ng/ml) as a predictor of mortality rate
time frame: from study entry to 6 months later
measure: Correlation of antibiotic prophylaxis use versus placebo on the rate of infections
time frame: from study entry to 6 months later
measure: Correlation of antibiotic prophylaxis use versus placebo on the mortality rate
time frame: from study entry to 6 months later
arm group label: treatment arm
arm group type: Experimental
description: Subjects allocated to the treatment arm of the study will be administrated Levofloxacin 500mg/d given p.o. once a day, starting on day 10 from beginning of each cycle until day 28 on an ambulatory basis. Levofloxacin will be continued in the first 4 Azacytidine cycles.
arm group label: placebo
arm group type: Placebo Comparator
description: Subject allocated to the placebo arm will be treated with placebo once a day, starting on day 10 from beginning until day 28 of each of the first 4 cycles.
intervention type: Drug
intervention name: Levofloxacin
description: one tablet (500mg) a day, from day 10 to day 28 in every cycle of the 4 first cycles
arm group label: treatment arm
other name: levo, tavanic
intervention type: Drug
intervention name: Placebo Oral Tablet
description: one tablet a day, from day 10 to day 28 in every cycle of the 4 first cycles
arm group label: placebo
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Drorit G Merkel, MD
role: Principal Investigator
affiliation: Sheba Medical Center
last name: Drorit G Merkel, MD
phone: 972526669168
email: drorit.merkel@sheba.health.gov.il
last name: Yshai Ofran, MD
phone: 972-50-2061524
email: y_ofran@rambam.health.gov.il
facility: 
status: Recruiting
contact: 
country: Israel
responsible party type: Principal Investigator
investigator affiliation: Sheba Medical Center
investigator full name: Dr. Drorit Merkel
investigator title: Principal Investigator
mesh term: Levofloxacin
sharing ipd: No