<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/NCT03279133</url>
  </required_header>
  <id_info>
    <org_study_id>IN-US-337-2116</org_study_id>
    <nct_id>NCT03279133</nct_id>
  </id_info>
  <brief_title>Ledipasvir/Sofosbuvir Treatment for Hepatitis C in HCT Recipients.</brief_title>
  <official_title>A Pilot/Feasibility Study of Ledipasvir/Sofosbuvir as Treatment for Hepatitis C in Hematopoietic Cell Transplantation (HCT) Recipients.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Kaiser Permanente</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>City of Hope National Medical Center</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Kaiser Permanente</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The prevalence of Hepatitis C Virus (HCV) infection was reported to range between 10% and up&#xD;
      to 30% prior to institution of routine HCV screening in recipients of HCT (hematopoietic cell&#xD;
      transplantation). In an Italian prospective study 6% of HCT candidates were positive for HCV&#xD;
      RNA. HCV in recipients of HCT carries both short-term and long-term consequences. In the&#xD;
      short-term those with HCV after hematopoietic cell transplantation have been associated with&#xD;
      risk for sinusoidal obstruction syndrome especially in patients with some level of hepatic&#xD;
      dysfunction going in to the transplant. In addition, the type of conditioning chemotherapy&#xD;
      (e.g., busulfan) and radiation may increase risk for sinusoidal obstruction syndrome. The&#xD;
      rate of hematopoietic recovery was found to be lower in HCV infected recipients, with delayed&#xD;
      neutrophil and platelet engraftment.&#xD;
&#xD;
      In the long-term, HCV may flare up once immunosuppression is being tapered off. The issue of&#xD;
      reactivation of viral hepatitis (HBV and HCV) after HCT has been well documented. The risk&#xD;
      for HCV reactivation in allogenic HCT in one study was reported at 100% by 12 months after&#xD;
      HCT, with risk for death related to HCV of 8%. Also, of concern is rapid progression of liver&#xD;
      disease in long-term survivors of HCV+ HCT. In such patients, cumulative incidence of&#xD;
      cirrhosis has been reported in up to 11% and 24% at 15 and 20 years after HCT respectively.&#xD;
&#xD;
      Hepatitis C infection is associated with significant morbidity and mortality, due to the&#xD;
      short-term and long-term complications associated with it. Treatment of hepatitis C virus&#xD;
      with direct-acting antiviral (DAA) agents pre-hematopoietic cell transplantation (HCT) in&#xD;
      candidates with hepatitis C may lead to reduction of both short-term and long-term&#xD;
      complications from it.&#xD;
&#xD;
      Treatment with DAA's pre-HCT in candidates with hepatitis C would potentially prevent&#xD;
      complications of hepatitis C infection; prevent reactivation of hepatitis C post-HCT, prevent&#xD;
      delay in hematopoietic recovery (especially neutrophils and platelet), possibly reduce risk&#xD;
      for sinsusoidal obstruction syndrome, prevent relapse of malignancy that could be related to&#xD;
      hepatitis C (non-Hodgkin lymphoma), reduce non-relapse mortality and long-term complications&#xD;
      (cirrhosis).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is an open-label observational/ feasibility study to treat candidates for HCT infected&#xD;
      with hepatitis C prior to the transplantation to reduce the complications associated with&#xD;
      hepatitis C in the post-transplant setting.&#xD;
&#xD;
      The study will be conducted at Kaiser Permanente Los Angeles Medical Center and City of Hope&#xD;
      National Medical Center, Duarte, CA.&#xD;
&#xD;
      There is no data available on the outcomes of treating hepatitis C with DAA's pre-HCT in&#xD;
      candidates with hepatitis C infection. The ASBMT task force made recommendation to consider&#xD;
      treating hepatitis C infection pre-HCT based on potential benefits it may be associated with.&#xD;
      A single case report has documented benefit of treating a donor infected with hepatitis C&#xD;
      prior to stem cell collection with DAA and ribavirin&#xD;
&#xD;
      Subject Population will include autologous or allogeneic HCT candidates (for hematologic&#xD;
      malignancy) who have hepatitis C infection. Subjects will be considered treatment-experienced&#xD;
      if they have received prior interferon-based therapy. Treatment-experienced patients with&#xD;
      prior use of DAA(s) are excluded from study participation.&#xD;
&#xD;
      This study will treat HCV patients prior to HCT, with the goal of reducing early post HCT&#xD;
      complications in the first 100 days post HCT followed by measuring outcomes at 2 years post&#xD;
      HCT.&#xD;
&#xD;
      Subjects will receive LDV 90mg/SOF 400mg FDC for 12 weeks.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Unable to find eligible patients with untreated hepatitis C virus.&#xD;
  </why_stopped>
  <start_date type="Actual">September 1, 2017</start_date>
  <completion_date type="Actual">April 29, 2018</completion_date>
  <primary_completion_date type="Actual">February 16, 2018</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>This is an open-label pilot, safety, feasibility study to treat candidates for HCT infected with hepatitis C prior to the transplantation to reduce the complications associated with hepatitis C in the post-transplant setting.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety and Tolerability of LDV/SOF Treatment in Candidates for HCT with hepatitis C infection</measure>
    <time_frame>2 year</time_frame>
    <description>To assess the safety and tolerability/feasibility of the two agent combination, ledipasvir and sofosbuvir (LDV/SOF), through evaluation of toxicities, including type frequency, severity, attribution, time course and duration.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Rate of HCV Relapse Post HCT</measure>
    <time_frame>2 Years</time_frame>
    <description>To estimate the rate of hepatitis C relapse post HCT - until 2 year after HCT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Effect of Virologic Suppression on Post HCT Complications</measure>
    <time_frame>2 Years</time_frame>
    <description>To evaluate the effect of virologic cure on the short term complications after HCT: hematopoietic recovery (neutrophil and platelet count), liver test abnormality, sinusoidal obstruction syndrome, liver disease decompensation in those with advanced fibrosis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of Patients with Sustained Virologic Response at Time of Transplant</measure>
    <time_frame>2 Years</time_frame>
    <description>To estimate the proportion of patients who attained SVR by the time of transplantation (day 0 of HCT), and remain HCV negative at day 30, day 100, day 180, year 1 and year 2 post HCT</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative Incidence of HCV Relapse</measure>
    <time_frame>2 Years</time_frame>
    <description>To estimate the cumulative incidence of hepatitis C relapse</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression of Liver Fibrosis After Transplant</measure>
    <time_frame>2 years</time_frame>
    <description>Monitoring for progression of liver fibrosis post-HCT compared to baseline (prior to initiation of DAA treatment)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Hematopoietic Stem Cell Transplantation</condition>
  <arm_group>
    <arm_group_label>LDV/SOF for 12 weeks.</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ledipasvir 90mg/Sofosubvir 400mg fixed-dose combination (FDC) tablet for 12 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ledipasvir 90mg/Sofosubvir 400mg</intervention_name>
    <description>Ledipasvir 90mg/Sofosubvir 400mg (LDV/SOF) FDC is to be administered once daily with or without food for12 weeks.</description>
    <arm_group_label>LDV/SOF for 12 weeks.</arm_group_label>
    <other_name>Harvoni</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Participant must be male or female at least 18 years of age at time of screening&#xD;
&#xD;
          2. Participant must be able to provide written Informed Consent&#xD;
&#xD;
          3. Participant must be able to adhere to study visit/procedure schedule and protocol&#xD;
             requirements&#xD;
&#xD;
          4. Time available (at least 12 weeks) for treatment of hepatitis C prior to autologous or&#xD;
             allogeneic transplantation&#xD;
&#xD;
          5. First autologous or allogeneic HCT and hematologic disease in remission on initiation&#xD;
             of antiviral therapy for hepatitis C infection&#xD;
&#xD;
          6. Patients with myelodysplastic syndrome, aplastic anemia or hemoglobinopathies will be&#xD;
             eligible to participate regardless of disease status if plan is to proceed to HCT&#xD;
&#xD;
          7. Female participant without childbearing potential must meet at least one of the&#xD;
             following:&#xD;
&#xD;
               -  Postmenopausal defined as women &gt;54 years of age with amenorrhea for ≥ 2 years&#xD;
                  prior to screening&#xD;
&#xD;
               -  Surgically sterile defined as bilateral tubal ligation or bilateral oophorectomy&#xD;
                  or hysterectomy&#xD;
&#xD;
               -  Has male sexual partner with vasectomy&#xD;
&#xD;
          8. Female participant of childbearing potential must meet at least one of the following:&#xD;
&#xD;
               -  Must be using at least 1 effective contraceptive method at screening and agree to&#xD;
                  practice 2 effective contraceptive methods1 for study duration, starting&#xD;
                  Screening through 30 days after stopping study drug&#xD;
&#xD;
               -  Practice total abstinence from sexual intercourse (minimum 1 complete menstrual&#xD;
                  cycle)&#xD;
&#xD;
               -  Sexually active with female partner only&#xD;
&#xD;
          9. Male participant who is not surgically sterile and is sexually active with female&#xD;
             partner of childbearing potential must agree to practice 2 effective contraceptive&#xD;
             methods1 for study duration, starting at Screening through 30 days after stopping&#xD;
             study drug&#xD;
&#xD;
         10. Participant must have the following indicator- of chronic hepatitis C virus infection&#xD;
             prior to study enrollment:&#xD;
&#xD;
             • Positive for HCV RNA at the time of screening&#xD;
&#xD;
         11. Participant screening laboratory result must indicate HCV genotype 1, 4, 5 or&#xD;
             6-infection if historical result is not available.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Participant unwilling to provide written informed consent&#xD;
&#xD;
          2. Participant unwilling to adhere to study visit/procedure schedule and protocol&#xD;
             requirements&#xD;
&#xD;
          3. Participant is pregnant or is a breastfeeding female&#xD;
&#xD;
          4. Positive test result for hepatitis B surface antigen (HBsAG), hepatitis B core&#xD;
             antibody (HBcAb), or confirmed positive anti-HIV antibody test&#xD;
&#xD;
          5. Received study contraindicated medications prior to study drug administration&#xD;
             including but not limited to those listed in the Full Prescribing Information Sheet&#xD;
             for ledipasvir/sofosbuvir (Harvoni®).&#xD;
&#xD;
          6. Clinically significant abnormalities or co-morbidities, other than HCV infection that&#xD;
             in opinion of the investigator makes subject unsuitable for this study or drug regimen&#xD;
&#xD;
          7. Prior or current use of any investigational or commercially available anti-HCV agents&#xD;
             other than interferon or ribavirin or receipt of any investigational product within 6&#xD;
             weeks prior to study drug administration&#xD;
&#xD;
          8. Prior treatment of chronic HCV infection with a direct acting antiviral agent(s):&#xD;
             telaprevir, boceprevir, sofosbuvir, simeprevir, or other direct acting antiviral&#xD;
&#xD;
          9. History of solid organ transplant&#xD;
&#xD;
         10. Screening laboratory analyses shows any of the following abnormal laboratory results:&#xD;
&#xD;
             Estimated Glomerular filtration (eGFR) rate &lt; 30 mL/min&#xD;
&#xD;
         11. Evidence of cirrhosis, documented by one of the following:&#xD;
&#xD;
             Liver biopsy histologic diagnosis: Metavir Score greater than 3 (includes 3 - 4 or ¾)&#xD;
             or Ishak score greater than 4 In the absence of liver biopsy: a FibroScan score&#xD;
             greater than or equal to 12.5 kPa or Fibrotest score of &gt;0.75 AND an APRI score&#xD;
             greater than 1.5&#xD;
&#xD;
         12. History of liver decompensation: ascites noted on a physical exam, imaging or other&#xD;
             test; variceal bleeding; hepatic encephalopathy&#xD;
&#xD;
         13. Confirmed presence of hepatocellular carcinoma indicated on computed tomography,&#xD;
             magnetic resonance, or other imaging techniques within 3 months prior to screening&#xD;
&#xD;
         14. HCV genotype performed during screening indicates infection with genotype 2 or 3&#xD;
&#xD;
         15. Recent history of drug or alcohol abuse that could, in the opinion of the&#xD;
             investigator, affect adherence to the study protocol&#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>Amandeep Sahota, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Kaiser Permanente</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>City of Hope</name>
      <address>
        <city>Duarte</city>
        <state>California</state>
        <zip>91010</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kaiser Permanente Los Angeles Medical Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90027</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2018</verification_date>
  <study_first_submitted>September 8, 2017</study_first_submitted>
  <study_first_submitted_qc>September 8, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 12, 2017</study_first_posted>
  <last_update_submitted>August 28, 2018</last_update_submitted>
  <last_update_submitted_qc>August 28, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">August 31, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hepatitis C</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Ledipasvir</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03279133
org study id: IN-US-337-2116
nct id: NCT03279133
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The prevalence of Hepatitis C Virus (HCV) infection was reported to range between 10% and up
      to 30% prior to institution of routine HCV screening in recipients of HCT (hematopoietic cell
      transplantation). In an Italian prospective study 6% of HCT candidates were positive for HCV
      RNA. HCV in recipients of HCT carries both short-term and long-term consequences. In the
      short-term those with HCV after hematopoietic cell transplantation have been associated with
      risk for sinusoidal obstruction syndrome especially in patients with some level of hepatic
      dysfunction going in to the transplant. In addition, the type of conditioning chemotherapy
      (e.g., busulfan) and radiation may increase risk for sinusoidal obstruction syndrome. The
      rate of hematopoietic recovery was found to be lower in HCV infected recipients, with delayed
      neutrophil and platelet engraftment.

      In the long-term, HCV may flare up once immunosuppression is being tapered off. The issue of
      reactivation of viral hepatitis (HBV and HCV) after HCT has been well documented. The risk
      for HCV reactivation in allogenic HCT in one study was reported at 100% by 12 months after
      HCT, with risk for death related to HCV of 8%. Also, of concern is rapid progression of liver
      disease in long-term survivors of HCV+ HCT. In such patients, cumulative incidence of
      cirrhosis has been reported in up to 11% and 24% at 15 and 20 years after HCT respectively.

      Hepatitis C infection is associated with significant morbidity and mortality, due to the
      short-term and long-term complications associated with it. Treatment of hepatitis C virus
      with direct-acting antiviral (DAA) agents pre-hematopoietic cell transplantation (HCT) in
      candidates with hepatitis C may lead to reduction of both short-term and long-term
      complications from it.

      Treatment with DAA's pre-HCT in candidates with hepatitis C would potentially prevent
      complications of hepatitis C infection; prevent reactivation of hepatitis C post-HCT, prevent
      delay in hematopoietic recovery (especially neutrophils and platelet), possibly reduce risk
      for sinsusoidal obstruction syndrome, prevent relapse of malignancy that could be related to
      hepatitis C (non-Hodgkin lymphoma), reduce non-relapse mortality and long-term complications
      (cirrhosis).
This is an open-label observational/ feasibility study to treat candidates for HCT infected
      with hepatitis C prior to the transplantation to reduce the complications associated with
      hepatitis C in the post-transplant setting.

      The study will be conducted at Kaiser Permanente Los Angeles Medical Center and City of Hope
      National Medical Center, Duarte, CA.

      There is no data available on the outcomes of treating hepatitis C with DAA's pre-HCT in
      candidates with hepatitis C infection. The ASBMT task force made recommendation to consider
      treating hepatitis C infection pre-HCT based on potential benefits it may be associated with.
      A single case report has documented benefit of treating a donor infected with hepatitis C
      prior to stem cell collection with DAA and ribavirin

      Subject Population will include autologous or allogeneic HCT candidates (for hematologic
      malignancy) who have hepatitis C infection. Subjects will be considered treatment-experienced
      if they have received prior interferon-based therapy. Treatment-experienced patients with
      prior use of DAA(s) are excluded from study participation.

      This study will treat HCV patients prior to HCT, with the goal of reducing early post HCT
      complications in the first 100 days post HCT followed by measuring outcomes at 2 years post
      HCT.

      Subjects will receive LDV 90mg/SOF 400mg FDC for 12 weeks.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: This is an open-label pilot, safety, feasibility study to treat candidates for HCT infected with hepatitis C prior to the transplantation to reduce the complications associated with hepatitis C in the post-transplant setting.
primary purpose: Treatment
masking: None (Open Label)
measure: Safety and Tolerability of LDV/SOF Treatment in Candidates for HCT with hepatitis C infection
time frame: 2 year
description: To assess the safety and tolerability/feasibility of the two agent combination, ledipasvir and sofosbuvir (LDV/SOF), through evaluation of toxicities, including type frequency, severity, attribution, time course and duration.
measure: Rate of HCV Relapse Post HCT
time frame: 2 Years
description: To estimate the rate of hepatitis C relapse post HCT - until 2 year after HCT
measure: Effect of Virologic Suppression on Post HCT Complications
time frame: 2 Years
description: To evaluate the effect of virologic cure on the short term complications after HCT: hematopoietic recovery (neutrophil and platelet count), liver test abnormality, sinusoidal obstruction syndrome, liver disease decompensation in those with advanced fibrosis
measure: Proportion of Patients with Sustained Virologic Response at Time of Transplant
time frame: 2 Years
description: To estimate the proportion of patients who attained SVR by the time of transplantation (day 0 of HCT), and remain HCV negative at day 30, day 100, day 180, year 1 and year 2 post HCT
measure: Cumulative Incidence of HCV Relapse
time frame: 2 Years
description: To estimate the cumulative incidence of hepatitis C relapse
measure: Progression of Liver Fibrosis After Transplant
time frame: 2 years
description: Monitoring for progression of liver fibrosis post-HCT compared to baseline (prior to initiation of DAA treatment)
arm group label: LDV/SOF for 12 weeks.
arm group type: Experimental
description: Ledipasvir 90mg/Sofosubvir 400mg fixed-dose combination (FDC) tablet for 12 weeks.
intervention type: Drug
intervention name: Ledipasvir 90mg/Sofosubvir 400mg
description: Ledipasvir 90mg/Sofosubvir 400mg (LDV/SOF) FDC is to be administered once daily with or without food for12 weeks.
arm group label: LDV/SOF for 12 weeks.
other name: Harvoni
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Amandeep Sahota, MD
role: Principal Investigator
affiliation: Kaiser Permanente
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Hepatitis C
mesh term: Ledipasvir
sharing ipd: Undecided