<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/NCT03781414</url>
  </required_header>
  <id_info>
    <org_study_id>CCFZ533A2202</org_study_id>
    <secondary_id>2018-001836-24</secondary_id>
    <secondary_id>CCFZ533A2202</secondary_id>
    <nct_id>NCT03781414</nct_id>
  </id_info>
  <brief_title>Study of Efficacy, Safety, Tolerability, Pharmacokinetic (PK) and Pharmacodynamic (PD) of an Anti-CD40 Monoclonal Antibody, CFZ533, in Liver Transplant Recipients With Additional 12-month Follow-up and Long-term Extension</brief_title>
  <acronym>CONTRAIL I</acronym>
  <official_title>A 12-month, Open-label, Multicenter, Randomized, Safety, Efficacy, Pharmacokinetic (PK) and Pharmacodynamic (PD) Study of Two Regimens of Anti-CD40 Monoclonal Antibody, CFZ533 vs. Standard of Care Control, in Adult de Novo Liver Transplant Recipients With a 12-month Additional Follow-up and a Long-term Extension (CONTRAIL I)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Novartis</source>
  <oversight_info>
    <has_dmc>Yes</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 purpose of this study was to investigate the safety, efficacy, pharmacokinetics (PK) and&#xD;
      pharmacodynamics (PD) of two CFZ533 dose regimens in liver transplant recipients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This study allowed assessment of the ability of CFZ533 to replace Calcineurin inhibitors&#xD;
      (CNIs) in terms of anti-rejection efficacy, while providing potentially better renal function&#xD;
      with an expected similar safety and tolerability profile. Results of this study will inform&#xD;
      the CFZ533 dose and regimen selection for investigation in later phases of clinical&#xD;
      development.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 7, 2019</start_date>
  <completion_date type="Actual">April 20, 2023</completion_date>
  <primary_completion_date type="Actual">April 20, 2023</primary_completion_date>
  <phase>Phase 2</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>
    <intervention_model_description>Study CCFZ533A2202 is a randomized, 12-month, active-controlled, multicenter, dose range finding study to evaluate the efficacy, safety, tolerability, PK and PD of CFZ533, as compared to standard of care comprised of tacrolimus, MMF and corticosteroids, with a 12-month additional follow up.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of patients with composite event (BPAR, Graft Loss or Death) over 12 months</measure>
    <time_frame>Baseline to Month 12</time_frame>
    <description>Rate of composite efficacy failure</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To mean eGFR up to Month 24 post-transplantation</measure>
    <time_frame>Baseline to month 24</time_frame>
    <description>Renal function at Month 24 measured by Estimated Glomerular Filtration Rate (eGFR)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with AEs and SAEs</measure>
    <time_frame>Baseline to month 12 and month 24</time_frame>
    <description>Proportion of patients with AEs, SAEs, AEs related to study drug</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of patients with premature discontinuation from study and premature discontinuation of study drug</measure>
    <time_frame>Baseline to month 12 and month 24</time_frame>
    <description>Tolerability assessment by rate of premature discontinuation from study, premature discontinuation of study drug, dose interruption and dose adjustment</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">129</enrollment>
  <condition>Liver Transplant Rejection</condition>
  <arm_group>
    <arm_group_label>Arm 1</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Control/Standard of Care: TAC + MMF + Corticosteroids</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>CFZ533 600mg dose + MMF + Corticosteroids</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>CFZ533 300mg dose + MMF + Corticosteroids</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>CFZ533</intervention_name>
    <description>Comparison with standard of care immunosuppression</description>
    <arm_group_label>Arm 2</arm_group_label>
    <arm_group_label>Arm 3</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Tacrolimus - MMF - corticosteroids</intervention_name>
    <description>Standard of care immunosupprevive regimen</description>
    <arm_group_label>Arm 1</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Screening period up to liver transplantation: -Written informed consent obtained before any&#xD;
        assessment.&#xD;
&#xD;
          -  Male or female subjects between 18 to 70 years of age.&#xD;
&#xD;
          -  Recipients of a primary liver transplant from a deceased donor.&#xD;
&#xD;
          -  Up to date vaccination as per local immunization schedules.&#xD;
&#xD;
          -  Recipients tested negative for HIV.&#xD;
&#xD;
          -  MELD score ≤30.&#xD;
&#xD;
        At randomization:&#xD;
&#xD;
          -  Recipients with no active HCV and HBV replication (no detectable RNA/DNA by PCR).&#xD;
&#xD;
          -  Allograft is functioning at an acceptable level by the time of randomization as&#xD;
             defined by AST, ALT, Alkaline Phosphatase levels ≤ 5 times ULN and Total bilirubin ≤ 2&#xD;
             times ULN.&#xD;
&#xD;
          -  Renal function (eGFR, MDRD-4 formula) ≥ 30 mL/min/1.73 m2 based on most recent&#xD;
             post-transplant value prior to randomization.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Screening period up to liver transplantation:&#xD;
&#xD;
          -  Recipients of a liver from a donor after cardiac death (DCD), from a living donor, or&#xD;
             of a split liver.&#xD;
&#xD;
          -  A negative Epstein Barr virus (EBV) test.&#xD;
&#xD;
          -  Recipients receiving an ABO incompatible allograft.&#xD;
&#xD;
          -  History of malignancy of any organ system treated or untreated, within the past 5&#xD;
             years.&#xD;
&#xD;
          -  Hepatocellular carcinoma that does not fulfill Milan criteria.&#xD;
&#xD;
          -  Recipients transplanted for acute liver failure.&#xD;
&#xD;
          -  Any use of antibody induction therapy, or use of any immunosuppressive medications&#xD;
&#xD;
          -  Patients who have received a live vaccine within four weeks prior to transplantation.&#xD;
&#xD;
          -  Recipients with donors HIV positive, HBsAg positive, HCV positive.&#xD;
&#xD;
          -  Recipients with donors with hepatic steatosis &gt; 30%.&#xD;
&#xD;
        At randomization:&#xD;
&#xD;
          -  Any post-transplant history of thrombosis, occlusion or stent placement in any hepatic&#xD;
             arteries, hepatic veins, portal vein or inferior vena cava at any time during the&#xD;
             run-in period prior to randomization.&#xD;
&#xD;
          -  Recipients with platelet count &lt; 50,000/mm3, an absolute neutrophil count of &lt;&#xD;
             1,000/mm³ or white blood cell count of &lt; 2,000/mm³.&#xD;
&#xD;
          -  Recipients with clinically significant systemic infection requiring use of intravenous&#xD;
             (IV) antibiotics.&#xD;
&#xD;
          -  Evidence of active tuberculosis (TB) infection.&#xD;
&#xD;
          -  Any episode of acute rejection or suspected rejection prior to randomization.&#xD;
&#xD;
          -  HCC participants whose explanted liver graft pathology report shows i) pTNM stage&#xD;
             beyond T2N0M0, ii) presence of mixed carcinoma, iii) microvascular invasion despite&#xD;
             pTNM stage.&#xD;
&#xD;
          -  Participants with body weight &amp;lt; 30 kg or &amp;gt; 180 kg.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Aurora</city>
        <state>Colorado</state>
        <zip>80045</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Detroit</city>
        <state>Michigan</state>
        <zip>48202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45267</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Charleston</city>
        <state>South Carolina</state>
        <zip>29425</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Caba</city>
        <state>Buenos Aires</state>
        <zip>C1118AAT</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Caba</city>
        <state>Buenos Aires</state>
        <zip>C1181ACH</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Caba</city>
        <state>Buenos Aires</state>
        <zip>C1280AEB</zip>
        <country>Argentina</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Gent</city>
        <zip>9000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Praha 4</city>
        <state>Czech Republic</state>
        <zip>140 21</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Chambray les Tours</city>
        <zip>37044</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Lille Cedex</city>
        <zip>59 037</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Montpellier</city>
        <zip>34295</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Villejuif</city>
        <zip>94805</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Regensburg</city>
        <state>Bavaria</state>
        <zip>93053</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Berlin</city>
        <zip>13353</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Hamburg</city>
        <zip>20246</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Muenster</city>
        <zip>48149</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Budapest</city>
        <zip>1085</zip>
        <country>Hungary</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Pisa</city>
        <state>PI</state>
        <zip>56124</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Rotterdam</city>
        <zip>3015 CE</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Sevilla</city>
        <state>Andalucia</state>
        <zip>41013</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>L Hospitalet De Llobregat</city>
        <state>Cataluna</state>
        <zip>08907</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Barcelona</city>
        <state>Catalunya</state>
        <zip>08036</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Madrid</city>
        <zip>28009</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Argentina</country>
    <country>Belgium</country>
    <country>Czechia</country>
    <country>France</country>
    <country>Germany</country>
    <country>Hungary</country>
    <country>Italy</country>
    <country>Netherlands</country>
    <country>Spain</country>
    <country>United States</country>
  </location_countries>
  <removed_countries>
    <country>United Kingdom</country>
  </removed_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>December 18, 2018</study_first_submitted>
  <study_first_submitted_qc>December 18, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 19, 2018</study_first_posted>
  <last_update_submitted>July 12, 2023</last_update_submitted>
  <last_update_submitted_qc>July 12, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 14, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Liver transplantation</keyword>
  <keyword>de novo recipients</keyword>
  <keyword>deceased donor</keyword>
  <keyword>CFZ533</keyword>
  <keyword>CNI-free immunosuppression</keyword>
  <keyword>Transplant rejection</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tacrolimus</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations.&#xD;
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com</ipd_description>
  </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/NCT03781414
org study id: CCFZ533A2202
secondary id: 2018-001836-24
secondary id: CCFZ533A2202
nct id: NCT03781414
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study was to investigate the safety, efficacy, pharmacokinetics (PK) and
      pharmacodynamics (PD) of two CFZ533 dose regimens in liver transplant recipients.
This study allowed assessment of the ability of CFZ533 to replace Calcineurin inhibitors
      (CNIs) in terms of anti-rejection efficacy, while providing potentially better renal function
      with an expected similar safety and tolerability profile. Results of this study will inform
      the CFZ533 dose and regimen selection for investigation in later phases of clinical
      development.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Study CCFZ533A2202 is a randomized, 12-month, active-controlled, multicenter, dose range finding study to evaluate the efficacy, safety, tolerability, PK and PD of CFZ533, as compared to standard of care comprised of tacrolimus, MMF and corticosteroids, with a 12-month additional follow up.
primary purpose: Treatment
masking: None (Open Label)
measure: Proportion of patients with composite event (BPAR, Graft Loss or Death) over 12 months
time frame: Baseline to Month 12
description: Rate of composite efficacy failure
measure: To mean eGFR up to Month 24 post-transplantation
time frame: Baseline to month 24
description: Renal function at Month 24 measured by Estimated Glomerular Filtration Rate (eGFR)
measure: Proportion of patients with AEs and SAEs
time frame: Baseline to month 12 and month 24
description: Proportion of patients with AEs, SAEs, AEs related to study drug
measure: Proportion of patients with premature discontinuation from study and premature discontinuation of study drug
time frame: Baseline to month 12 and month 24
description: Tolerability assessment by rate of premature discontinuation from study, premature discontinuation of study drug, dose interruption and dose adjustment
arm group label: Arm 1
arm group type: Active Comparator
description: Control/Standard of Care: TAC + MMF + Corticosteroids
arm group label: Arm 2
arm group type: Experimental
description: CFZ533 600mg dose + MMF + Corticosteroids
arm group label: Arm 3
arm group type: Experimental
description: CFZ533 300mg dose + MMF + Corticosteroids
intervention type: Biological
intervention name: CFZ533
description: Comparison with standard of care immunosuppression
arm group label: Arm 2
arm group label: Arm 3
intervention type: Drug
intervention name: Tacrolimus - MMF - corticosteroids
description: Standard of care immunosupprevive regimen
arm group label: Arm 1
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
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country: Argentina
country: Belgium
country: Czechia
country: France
country: Germany
country: Hungary
country: Italy
country: Netherlands
country: Spain
country: United States
country: United Kingdom
responsible party type: Sponsor
mesh term: Tacrolimus
sharing ipd: Yes
ipd description: Novartis is committed to sharing access to patient-level data and supporting clinical documents from eligible studies with qualified external researchers. Requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to protect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com