<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/NCT04439916</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00093295</org_study_id>
    <nct_id>NCT04439916</nct_id>
  </id_info>
  <brief_title>Breakthrough CMV Lung Transplant -Multicentre</brief_title>
  <official_title>Breakthrough CMV DNAemia in CMV Seronegative Recipients of CMV Seropositive Lung Transplantation During Antiviral Prophylaxis With Valganciclovir. A Pilot Study.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Alberta</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Alberta</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>
      Cytomegalovirus (CMV) infection is the most common opportunistic infection in lung&#xD;
      transplantation leading to direct and indirect effects that can result in life threatening&#xD;
      complications. The risk of CMV infection is highest when the recipient of the transplant has&#xD;
      never been in contact with CMV (negative immunity) and the donor had previous contact with&#xD;
      CMV (positive immunity). This is called CMV mismatch. For these lung transplant patients 6 to&#xD;
      12 months of prophylaxis with an antiviral called Valganciclovir is recommended. This&#xD;
      antiviral can cause side effects like bone marrow toxicity and decrease in immune cells which&#xD;
      can result in temporarily having to stop the treatment. Starting and stopping the prophylaxis&#xD;
      may result in the CMV becoming resistant to the medication. While taking the prophylaxis it&#xD;
      is possible to have a breakthrough of the CMV, this is often due to the development of&#xD;
      resistance to the antiviral. The purpose of this study is to learn more about the rate of CMV&#xD;
      breakthrough while on prophylaxis after lung transplantation in patients who are CMV&#xD;
      mismatch. The investigators will also look at the rates of negative side effects caused by&#xD;
      antiviral prophylaxis in this population.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Purpose:&#xD;
&#xD;
      The purpose of this study is to learn more about the rate of CMV breakthrough in lung&#xD;
      transplant patients who are CMV mismatched and receiving prophylaxis. The rates of negative&#xD;
      side effects caused by the antiviral prophylaxis will also be monitored. For patients who do&#xD;
      have a breakthrough of CMV viremia while on study the investigator will also evaluate the&#xD;
      rate of resistance mutations.&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
      The investigator wants to demonstrate that breakthrough CMV DNAemia is common in CMV mismatch&#xD;
      lung transplant recipients on ganciclovir/valganciclovir prophylaxis. In addition, the&#xD;
      investigator will show that leukopenia and neutropenia related to prolonged prophylaxis is&#xD;
      very common and discontinuation of ganciclovir/valganciclovir prophylaxis because of side&#xD;
      effects explains most cases of breakthrough CMV DNAemia. The investigators findings will be&#xD;
      relevant because they will answer the following questions:&#xD;
&#xD;
        1. Prophylaxis with ganciclovir/valganciclovir in mismatch lung transplant patients should&#xD;
           include intensive CMV DNA monitoring.&#xD;
&#xD;
        2. Side effects related to the use of ganciclovir/valganciclovir can result in potential&#xD;
           life-threatening infections due to the development of neutropenia and increased cost due&#xD;
           to the use of granulocyte-colony stimulating factor.&#xD;
&#xD;
        3. Alternative prophylaxis with new antivirals with safer profile of side effects would&#xD;
           result in a safer profile of adverse events. As resistance to ganciclovir may lead to&#xD;
           death, the development of CMV infection in patients receiving antivirals targeting&#xD;
           different enzymes than those targeted by ganciclovir/valganciclovir will not prevent&#xD;
           future use of ganciclovir/valganciclovir to treat CMV infection or disease.&#xD;
&#xD;
      Justification:&#xD;
&#xD;
      Cytomegalovirus (CMV) infection is the most common opportunistic infection in lung&#xD;
      transplantation leading to direct and indirect effects that can result in life threatening&#xD;
      complications. The risk of CMV infection is highest in CMV seronegative lung recipients from&#xD;
      CMV seropositive donor (CMV mismatch). Antiviral prophylaxis for 6 to12 months with&#xD;
      valganciclovir is indicated in CMV mismatch lung transplant recipients according to&#xD;
      International Guidelines. Despite prolonged antiviral prophylaxis, the risk of CMV infection&#xD;
      post-prophylaxis is high in this group of patients. Valganciclovir was approved for antiviral&#xD;
      prophylaxis in organ transplant patients in 2004. Rates of breakthrough CMV infection may be&#xD;
      higher after 6 months of prophylaxis due to an increased risk of bone marrow toxicity and&#xD;
      neutropenia from Valganciclovir that may lead to temporary prophylaxis discontinuation.&#xD;
&#xD;
      Resistance to ganciclovir is a major complication in all solid organ transplant patients, but&#xD;
      lung transplant recipients are the subgroup of patients at highest risk. The rate of&#xD;
      ganciclovir-resistant CMV infection in CMV mismatch lung transplant recipients is the highest&#xD;
      among all organ transplants and its occurrence is associated with increased risk of death.&#xD;
      Although CMV mismatch lung transplantation has been found to be a risk factor for&#xD;
      ganciclovir-resistant CMV infection in most of the studies, the underlying pathophysiological&#xD;
      mechanisms are not fully understood. Discontinuation of valganciclovir can lead to CMV&#xD;
      replication with exposure to sub-therapeutic levels of ganciclovir in blood, and this may&#xD;
      lead to the development of antiviral resistance.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
        1. To evaluate the incidence of breakthrough CMV infection in CMV mismatch lung transplant&#xD;
           patients receiving 6-12 months antiviral prophylaxis with ganciclovir/valganciclovir.&#xD;
&#xD;
        2. To evaluate the rates of leukopenia, neutropenia and antiviral prophylaxis&#xD;
           discontinuation due to side effects of antiviral prophylaxis with&#xD;
           ganciclovir/valganciclovir in CMV mismatch lung transplant patients.&#xD;
&#xD;
        3. To evaluate the rates of ganciclovir/valganciclovir resistance mutations in CMV DNA from&#xD;
           mismatch lung transplant patients with breakthrough CMV viremia.&#xD;
&#xD;
      Research Method/Procedures:&#xD;
&#xD;
      This will be a prospective, multicenter, non-randomized, non-interventional study in 40 CMV&#xD;
      mismatch lung transplant patients receiving standard of care prophylaxis according to each&#xD;
      center. At baseline the patients medical history will be reviewed with them. Post transplant&#xD;
      weeks 1 to 24 or 52 a CMV Polymerase chain reaction (PCR) will be done every two weeks.&#xD;
      Standard of care blood work and the patients chart will be monitored to look for any relevant&#xD;
      side effects or changes in medication. In case CMV viremia is detected during prophylaxis,&#xD;
      the local PI can decide either to treat the CMV infection with therapeutic dose of antivirals&#xD;
      (ganciclovir, valganciclovir or Foscarnet) or to maintain prophylaxis and CMV PCR monitoring.&#xD;
      In all cases of CMV breakthrough viremia, a whole blood or plasma sample will be sent to&#xD;
      Provincial Microbiology Lab in Edmonton to perform antiviral resistance by next-generation&#xD;
      sequencing. From post transplant weeks 24 to 36 or 52 to 64 weekly CMV PCR will be done as&#xD;
      per standard of care, all other standard of care blood work will also be monitored. Chart&#xD;
      reviews will be completed to look for any relevant side effects.&#xD;
&#xD;
      Plan for Data Analysis:&#xD;
&#xD;
      For the analysis of data the investigator will have the support of the Northern Alberta&#xD;
      Clinical Trials and Research Centre (NACTRC). Incidence rate of breakthrough CMV viremia,&#xD;
      leukopenia, neutropenia and severe neutropenia will be calculated as number of case per 1,000&#xD;
      patients/week. The percentage of CMV infection post-prophylaxis in patients with and without&#xD;
      breakthrough CMV infection will be compared by Fisher's exact test. Cox-regression analysis&#xD;
      will be performed to identify independent variables associated with CMV breakthrough viremia.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 25, 2021</start_date>
  <completion_date type="Anticipated">December 2024</completion_date>
  <primary_completion_date type="Anticipated">July 2024</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>CMV Breakthrough</measure>
    <time_frame>Up to 52 weeks</time_frame>
    <description>Incidence of CMV infection (defined as any quantifiable CMV viral load in plasma or blood) during prophylaxis. Will be categorized as CMV asymptomatic infection or CMV disease.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>CMV infection</measure>
    <time_frame>12 weeks</time_frame>
    <description>Incidence of CMV infection post-prophylaxis (categorized as CMV infection or disease).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neutropenia</measure>
    <time_frame>through study completion, up to 64 weeks</time_frame>
    <description>Absolute neutrophil count &lt; 1,000 cells/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severe neutropenia</measure>
    <time_frame>through study completion, up to 64 weeks</time_frame>
    <description>Absolute neutrophil count &lt; 500 cells/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Leukopenia</measure>
    <time_frame>through study completion, up to 64 weeks</time_frame>
    <description>White cell count &lt; 2,000 cells/mL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Use of Granulocyte - colony stimulating factor (G-CSF)</measure>
    <time_frame>through study completion up, to 64 weeks</time_frame>
    <description>Whether a patient requires G-CSF</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CMV resistant infection</measure>
    <time_frame>through study completion, up to 64 weeks</time_frame>
    <description>Mutation in UL97, UL54 or both.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Opportunistic and non-opportunistic infections</measure>
    <time_frame>through study completion, up to 64 weeks</time_frame>
    <description>All incidence of other infections</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Chronic lung allograft dysfunction</measure>
    <time_frame>through study completion, up to 64 weeks</time_frame>
    <description>All incidence of chronic lung allograft dysfunction will be captured.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Retransplantation</measure>
    <time_frame>through study completion, up to 64 weeks</time_frame>
    <description>Any incidence where retransplantation is required</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Death</measure>
    <time_frame>through study completion, up to 64 weeks</time_frame>
    <description>Whether a patient dies during study</description>
  </secondary_outcome>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Cytomegalovirus Infections</condition>
  <eligibility>
    <study_pop>
      <textblock>
        Lung transplant patients, 18 years or older, who will receive either 6 or 12 months of&#xD;
        prophylaxis, are CMV seronegative and received a CMV seropositive transplant.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  CMV seronegative recipients of CMV seropositive donor lung transplantation.&#xD;
&#xD;
          -  Age 18 years or older.&#xD;
&#xD;
          -  Receipt of antiviral prophylaxis with valganciclovir as per local protocol with a&#xD;
             duration of 6 or 12 months after transplantation.&#xD;
&#xD;
          -  Monitoring of CMV DNAemia post-prophylaxis for at least 12 weeks as per local&#xD;
             protocol.&#xD;
&#xD;
          -  Signed informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Known allergy to ganciclovir or valganciclovir.&#xD;
&#xD;
          -  Neutropenia (&lt; 1.0) pre-transplantation.&#xD;
&#xD;
          -  Living-donor lung transplantation.&#xD;
&#xD;
          -  Lung re-transplantation.&#xD;
&#xD;
          -  Pre-transplant immunodeficiency&#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>Dr. Carlos Cervera</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Alberta</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Dr. Carlos Cervera</last_name>
    <phone>780-492-5346</phone>
    <email>cerveraa@ualberta.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Kimberly J Robertson, BSc</last_name>
    <phone>780-407-6945</phone>
    <email>kimberly.robertson2@ahs.ca</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University of Alberta Hospital</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>T6G 2B7</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kimberly J Robertson, BSc</last_name>
      <phone>780-407-6945</phone>
      <email>kimberly.robertson2@ahs.ca</email>
    </contact>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>June 8, 2020</study_first_submitted>
  <study_first_submitted_qc>June 17, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 19, 2020</study_first_posted>
  <last_update_submitted>June 5, 2023</last_update_submitted>
  <last_update_submitted_qc>June 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>CMV</keyword>
  <keyword>Lung transplant</keyword>
  <keyword>Valganciclovir</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cytomegalovirus Infections</mesh_term>
  </condition_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/NCT04439916
org study id: Pro00093295
nct id: NCT04439916
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Cytomegalovirus (CMV) infection is the most common opportunistic infection in lung
      transplantation leading to direct and indirect effects that can result in life threatening
      complications. The risk of CMV infection is highest when the recipient of the transplant has
      never been in contact with CMV (negative immunity) and the donor had previous contact with
      CMV (positive immunity). This is called CMV mismatch. For these lung transplant patients 6 to
      12 months of prophylaxis with an antiviral called Valganciclovir is recommended. This
      antiviral can cause side effects like bone marrow toxicity and decrease in immune cells which
      can result in temporarily having to stop the treatment. Starting and stopping the prophylaxis
      may result in the CMV becoming resistant to the medication. While taking the prophylaxis it
      is possible to have a breakthrough of the CMV, this is often due to the development of
      resistance to the antiviral. The purpose of this study is to learn more about the rate of CMV
      breakthrough while on prophylaxis after lung transplantation in patients who are CMV
      mismatch. The investigators will also look at the rates of negative side effects caused by
      antiviral prophylaxis in this population.
Purpose:

      The purpose of this study is to learn more about the rate of CMV breakthrough in lung
      transplant patients who are CMV mismatched and receiving prophylaxis. The rates of negative
      side effects caused by the antiviral prophylaxis will also be monitored. For patients who do
      have a breakthrough of CMV viremia while on study the investigator will also evaluate the
      rate of resistance mutations.

      Hypothesis:

      The investigator wants to demonstrate that breakthrough CMV DNAemia is common in CMV mismatch
      lung transplant recipients on ganciclovir/valganciclovir prophylaxis. In addition, the
      investigator will show that leukopenia and neutropenia related to prolonged prophylaxis is
      very common and discontinuation of ganciclovir/valganciclovir prophylaxis because of side
      effects explains most cases of breakthrough CMV DNAemia. The investigators findings will be
      relevant because they will answer the following questions:

        1. Prophylaxis with ganciclovir/valganciclovir in mismatch lung transplant patients should
           include intensive CMV DNA monitoring.

        2. Side effects related to the use of ganciclovir/valganciclovir can result in potential
           life-threatening infections due to the development of neutropenia and increased cost due
           to the use of granulocyte-colony stimulating factor.

        3. Alternative prophylaxis with new antivirals with safer profile of side effects would
           result in a safer profile of adverse events. As resistance to ganciclovir may lead to
           death, the development of CMV infection in patients receiving antivirals targeting
           different enzymes than those targeted by ganciclovir/valganciclovir will not prevent
           future use of ganciclovir/valganciclovir to treat CMV infection or disease.

      Justification:

      Cytomegalovirus (CMV) infection is the most common opportunistic infection in lung
      transplantation leading to direct and indirect effects that can result in life threatening
      complications. The risk of CMV infection is highest in CMV seronegative lung recipients from
      CMV seropositive donor (CMV mismatch). Antiviral prophylaxis for 6 to12 months with
      valganciclovir is indicated in CMV mismatch lung transplant recipients according to
      International Guidelines. Despite prolonged antiviral prophylaxis, the risk of CMV infection
      post-prophylaxis is high in this group of patients. Valganciclovir was approved for antiviral
      prophylaxis in organ transplant patients in 2004. Rates of breakthrough CMV infection may be
      higher after 6 months of prophylaxis due to an increased risk of bone marrow toxicity and
      neutropenia from Valganciclovir that may lead to temporary prophylaxis discontinuation.

      Resistance to ganciclovir is a major complication in all solid organ transplant patients, but
      lung transplant recipients are the subgroup of patients at highest risk. The rate of
      ganciclovir-resistant CMV infection in CMV mismatch lung transplant recipients is the highest
      among all organ transplants and its occurrence is associated with increased risk of death.
      Although CMV mismatch lung transplantation has been found to be a risk factor for
      ganciclovir-resistant CMV infection in most of the studies, the underlying pathophysiological
      mechanisms are not fully understood. Discontinuation of valganciclovir can lead to CMV
      replication with exposure to sub-therapeutic levels of ganciclovir in blood, and this may
      lead to the development of antiviral resistance.

      Objectives:

        1. To evaluate the incidence of breakthrough CMV infection in CMV mismatch lung transplant
           patients receiving 6-12 months antiviral prophylaxis with ganciclovir/valganciclovir.

        2. To evaluate the rates of leukopenia, neutropenia and antiviral prophylaxis
           discontinuation due to side effects of antiviral prophylaxis with
           ganciclovir/valganciclovir in CMV mismatch lung transplant patients.

        3. To evaluate the rates of ganciclovir/valganciclovir resistance mutations in CMV DNA from
           mismatch lung transplant patients with breakthrough CMV viremia.

      Research Method/Procedures:

      This will be a prospective, multicenter, non-randomized, non-interventional study in 40 CMV
      mismatch lung transplant patients receiving standard of care prophylaxis according to each
      center. At baseline the patients medical history will be reviewed with them. Post transplant
      weeks 1 to 24 or 52 a CMV Polymerase chain reaction (PCR) will be done every two weeks.
      Standard of care blood work and the patients chart will be monitored to look for any relevant
      side effects or changes in medication. In case CMV viremia is detected during prophylaxis,
      the local PI can decide either to treat the CMV infection with therapeutic dose of antivirals
      (ganciclovir, valganciclovir or Foscarnet) or to maintain prophylaxis and CMV PCR monitoring.
      In all cases of CMV breakthrough viremia, a whole blood or plasma sample will be sent to
      Provincial Microbiology Lab in Edmonton to perform antiviral resistance by next-generation
      sequencing. From post transplant weeks 24 to 36 or 52 to 64 weekly CMV PCR will be done as
      per standard of care, all other standard of care blood work will also be monitored. Chart
      reviews will be completed to look for any relevant side effects.

      Plan for Data Analysis:

      For the analysis of data the investigator will have the support of the Northern Alberta
      Clinical Trials and Research Centre (NACTRC). Incidence rate of breakthrough CMV viremia,
      leukopenia, neutropenia and severe neutropenia will be calculated as number of case per 1,000
      patients/week. The percentage of CMV infection post-prophylaxis in patients with and without
      breakthrough CMV infection will be compared by Fisher's exact test. Cox-regression analysis
      will be performed to identify independent variables associated with CMV breakthrough viremia.
observational model: Cohort
time perspective: Prospective
measure: CMV Breakthrough
time frame: Up to 52 weeks
description: Incidence of CMV infection (defined as any quantifiable CMV viral load in plasma or blood) during prophylaxis. Will be categorized as CMV asymptomatic infection or CMV disease.
measure: CMV infection
time frame: 12 weeks
description: Incidence of CMV infection post-prophylaxis (categorized as CMV infection or disease).
measure: Neutropenia
time frame: through study completion, up to 64 weeks
description: Absolute neutrophil count < 1,000 cells/mL
measure: Severe neutropenia
time frame: through study completion, up to 64 weeks
description: Absolute neutrophil count < 500 cells/mL
measure: Leukopenia
time frame: through study completion, up to 64 weeks
description: White cell count < 2,000 cells/mL
measure: Use of Granulocyte - colony stimulating factor (G-CSF)
time frame: through study completion up, to 64 weeks
description: Whether a patient requires G-CSF
measure: CMV resistant infection
time frame: through study completion, up to 64 weeks
description: Mutation in UL97, UL54 or both.
measure: Opportunistic and non-opportunistic infections
time frame: through study completion, up to 64 weeks
description: All incidence of other infections
measure: Chronic lung allograft dysfunction
time frame: through study completion, up to 64 weeks
description: All incidence of chronic lung allograft dysfunction will be captured.
measure: Retransplantation
time frame: through study completion, up to 64 weeks
description: Any incidence where retransplantation is required
measure: Death
time frame: through study completion, up to 64 weeks
description: Whether a patient dies during study
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Dr. Carlos Cervera
role: Principal Investigator
affiliation: University of Alberta
last name: Dr. Carlos Cervera
phone: 780-492-5346
email: cerveraa@ualberta.ca
last name: Kimberly J Robertson, BSc
phone: 780-407-6945
email: kimberly.robertson2@ahs.ca
facility: 
status: Recruiting
contact: 
country: Canada
responsible party type: Sponsor
mesh term: Cytomegalovirus Infections