<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/NCT04431219</url>
  </required_header>
  <id_info>
    <org_study_id>XT-1901</org_study_id>
    <nct_id>NCT04431219</nct_id>
  </id_info>
  <brief_title>First in Human Study: LIS1, an Induction Treatment in Kidney Transplanted Patients</brief_title>
  <official_title>First in Human Study for the Assessment of Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Multiple Ascending Intravenous Doses of LIS1 in Kidney Transplanted Patients</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Xenothera SAS</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Xenothera SAS</source>
  <oversight_info>
    <has_dmc>Yes</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>
      This first in human study aims at evaluating LIS1, a stabilized solution of purified anti-T&#xD;
      lymphocytes polyclonal glyco-humanized swine IgG with immunosuppressive activity, in regards&#xD;
      of safety, T cell depletion, and pharmacokinetics / pharmacodynamics in 10 kidney transplant&#xD;
      recipients.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 26, 2019</start_date>
  <completion_date type="Actual">March 28, 2022</completion_date>
  <primary_completion_date type="Actual">March 28, 2022</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>This is a phase I/II interventional, uncontrolled, single center, open-label study with an adaptive design conducted in two cohorts: Ascending Dose (AD) cohort and Therapeutic Dose (TD) cohort.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety of the treatment with LIS1: Blood pressure</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Clinical safety parameters (1): Systolic and diastolic blood pressure (mm Hg).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety of the treatment with LIS1: Pulse rate</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Clinical safety parameters (2): Pulse rate (beats per minute [bpm]) .</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety of the treatment with LIS1: Body temperature</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Clinical safety parameters (3): Body temperature (Celsius degrees).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety of the treatment with LIS1: Graft rejection</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Clinical safety parameters (4): Graft rejection (yes/no).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety of the treatment with LIS1: Infection</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Clinical safety parameters (5): Viral infections (namely Cytomegalovirus [CMV], BK virus) (yes/no).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety of the treatment with LIS1: Re-admission</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Clinical safety parameters (6): Re-admission after patient discharge (yes/no).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety of the treatment with LIS1: Hospitalization</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Clinical safety parameters (7): Prolonged stay in hospital for &gt;4 weeks (days).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety of the treatment with LIS1: CRP</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Laboratory parameters (1): C-Reactive Protein (CRP, mg/L).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety of the treatment with LIS1: LDH</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Laboratory parameters (2): Lactate Dehydrogenase (LDH, µkat/L).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety of the treatment with LIS1: aPTT</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Laboratory parameters (3): activated Partial Thromboplastin Time (aPTT, seconds).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety of the treatment with LIS1: Complete Blood Count (CBC)</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Laboratory parameters (4): Platelets (10^9/L), white blood cells (10^9/L), absolute neutrophil count (10^9/L), absolute lymphocyte count (10^9/L), absolute monocyte count (10^9/L), absolute eosinophil count (10^9/L), absolute basophil count (10^9/L).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Pharmacodynamics (depletion of T lymphocytes) of LIS1</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Absolute T lymphocyte counts (10^9/L).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetics of LIS1 (1): swine IgG</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Serum concentration of swine IgG</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacodynamics of LIS1 (2): cytokines</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Cytokine concentration (IL6, TNFα) (ng/mL).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biology of LIS1 (1): electrolytes plasma concentration</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Plasma biochemistry: electrolytes (Na+, K+, Cl-, Ca++, Mg++, bicarbonates plasma concentrations mmol/L)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biology of LIS1 (2): urea and creatinine</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Plasma biochemistry: urea and creatinine plasma concentration (mmol/L)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biology of LIS1 (3): total plasma proteins</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Plasma biochemistry: Total protein plasma concentration (g/L)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Biology of LIS1 (4): plasmatic proteins</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Plasma biochemistry: electrophoresis of plasmatic proteins (percentages of albumin, alpha-1-globulin, alpha-2-globulin, beta-globulin, gamma-globulin)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunogenicity of LIS1</measure>
    <time_frame>up to 3 months after the transplant</time_frame>
    <description>Detection of antidrug antibodies in serum</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Kidney Transplant</condition>
  <arm_group>
    <arm_group_label>Ascending Dose Cohort</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The AD cohort will be first recruited and will include 5 patients: 1 patient per dose, sequentially recruited, the recruitment of the next dose level patient will be assessed by Data Safety Monitoring Board :&#xD;
Patient 1: 0.6 mg/Kg/day&#xD;
Patient 2: 1 mg/Kg/day&#xD;
Patient 3: 3 mg/Kg/day&#xD;
Patient 4: 6 mg/Kg/day&#xD;
Patient 5: 8 mg/Kg/day&#xD;
Once the 5 AD patients complete LIS1 treatment, the sponsor and the DSMB will rule on the LIS1 dose to obtain an optimal CD3+ cells depletion, with a good safety profile and will determine the therapeutic dose.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Therapeutic Dose Cohort</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The TD cohort will be recruited once the therapeutic dose is defined. This cohort will be divided in 2 subgroups of respectively 2 and 3 patients sequentially recruited.&#xD;
DSMB will review the safety and efficacy profile of the first 2 patients (Subgroup1) and decide:&#xD;
To continue at the same dose and recruit the next 3 patients of Subgroup 2&#xD;
To recruit the next 3 patients with a lower dose, estimated from AD as bringing efficient depletion&#xD;
To recruit the next patient with a higher dose (+2 mg/kg), if the depletion is not considered satisfactory and if the safety profile is considered acceptable&#xD;
To end the trial if LIS1 toxicity is too important vs its efficacy in CD3+ depletion.&#xD;
If the decision to increase the dose after the first two TD patients is made, an additional DSMB review will be planned after patient 8. The DSMB will decide to maintain the dose for the last 2 patients or to get back to the previous dose</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>LIS1</intervention_name>
    <description>LIS1 is an induction treatment on top of maintenance immunosuppressive regimen. All patients from AD and TD cohort will receive the conventional immunosuppressive regimen: tacrolimus (0.2 mg/kg) / mycophenolic acid (MMF, 2x1000 mg) / prednisone (20 mg from day 2). This conventional treatment should be started and monitored for all patients independently of their participation in the clinical trial. Methylprednisolone 500 mg / 100 mL saline / 30 minutes will be administered before reperfusion during the surgery and on post operation day 1 just before LIS1 administration.</description>
    <arm_group_label>Ascending Dose Cohort</arm_group_label>
    <arm_group_label>Therapeutic Dose Cohort</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Participants must be listed for kidney transplantation,&#xD;
&#xD;
          -  AD cohort participants: First transplantation, Panel Reactive Antibody (PRA) &lt; 20%,&#xD;
             negative Donor Specific Antibody (DSA), no anti-HLA antibodies, Epstein-Barr Virus&#xD;
             positive (EBV+) serology,&#xD;
&#xD;
          -  TD cohort participants: First transplantation, 0-50 % PRA, negative DSA, negative flow&#xD;
             cytometry crossmatch (FCXM) for any patients with anti-HLA antibodies on screening is&#xD;
             mandatory, Epstein-Barr Virus positive (EBV+) serology&#xD;
&#xD;
          -  Participants must weigh at least 50 kg and have a Body Mass Index (BMI) 18.0 ≤ BMI &lt;&#xD;
             35.0 kg/m2,&#xD;
&#xD;
          -  White Blood Cells &gt; 3000/mm3, platelets &gt; 75000/mm3,&#xD;
&#xD;
          -  Female participants (WOCBP) must have a negative pregnancy test at screening and use a&#xD;
             highly effective birth control until 90 days after the last administration of study&#xD;
             drug,&#xD;
&#xD;
          -  Non-vasectomized male subjects having a female partner of childbearing potential must&#xD;
             agree to the use of a highly effective method of contraception until 90 days after the&#xD;
             last administration of study drug,&#xD;
&#xD;
          -  Participants must be capable of giving signed informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patients with an active cancer or a history of kidney cancer,&#xD;
&#xD;
          -  Patients who have previously been exposed to other anti-lymphocyte globulins,&#xD;
&#xD;
          -  Patients with previous organ transplantation,&#xD;
&#xD;
          -  Patients with a history of specific viral infection that would contraindicate&#xD;
             depleting antibody therapy (Hepatitis B and C, HIV),&#xD;
&#xD;
          -  Patients with a positive HIV and/or Hepatitis B and C tests&#xD;
&#xD;
          -  Patients who have uncontrolled concomitant bacterial or viral infections (unresolved&#xD;
             during screening), mycosis and/or parasitosis,&#xD;
&#xD;
          -  Patients with a significant liver function impairment: enzyme (AST and/or ALT) values&#xD;
             must not exceed 1.5 times upper limit of normal,&#xD;
&#xD;
          -  Patients with positive testing for tuberculosis (using QuantiFERON-TB test), Patients&#xD;
             with CMV D+/R- constellation at transplant,&#xD;
&#xD;
          -  Patients with seronegative EBV prior to transplantation,&#xD;
&#xD;
          -  Patients who have previously been exposed to antibodies of swine origin,&#xD;
&#xD;
          -  Expanded Criteria Donor (ECD) defined as donor older than 60 years,&#xD;
&#xD;
          -  Participants who have participated in another research study involving an&#xD;
             investigational product in the previous 3 months,&#xD;
&#xD;
          -  Patients with cardiovascular or severe respiratory comorbidities (severe chronic&#xD;
             respiratory failure, severe pulmonary fibrosis, obesity-ventilation syndrome, severe&#xD;
             idiopathic pulmonary arterial hypertension) not allowing general anesthesia,&#xD;
&#xD;
          -  Patients with type 1 diabetes,&#xD;
&#xD;
          -  Participants who are pregnant, breast feeding or planning pregnancy during the study,&#xD;
&#xD;
          -  Participants who have any form of substance abuse (drug, alcohol…), any other health&#xD;
             abnormalities (psychiatric disorders) or condition that according to the&#xD;
             investigator's opinion might endanger patient during his/her participation in the&#xD;
             study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dr Ondrej Viklicky</last_name>
    <role>Principal Investigator</role>
    <affiliation>Institut klinické a experimentální medicíny, Praha 4, Czech Republic</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Institut klinické a experimentální medicíny</name>
      <address>
        <city>Praha 4</city>
        <zip>140 21</zip>
        <country>Czechia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Czechia</country>
  </location_countries>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>May 28, 2020</study_first_submitted>
  <study_first_submitted_qc>June 10, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>August 16, 2022</last_update_submitted>
  <last_update_submitted_qc>August 16, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 17, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>immunosuppression</keyword>
  <keyword>polyclonal IgG</keyword>
  <keyword>allograft transplantation</keyword>
  <keyword>induction treatment</keyword>
  <keyword>acute graft rejection</keyword>
  <!-- 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/NCT04431219
org study id: XT-1901
nct id: NCT04431219
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This first in human study aims at evaluating LIS1, a stabilized solution of purified anti-T
      lymphocytes polyclonal glyco-humanized swine IgG with immunosuppressive activity, in regards
      of safety, T cell depletion, and pharmacokinetics / pharmacodynamics in 10 kidney transplant
      recipients.
allocation: Non-Randomized
intervention model: Sequential Assignment
intervention model description: This is a phase I/II interventional, uncontrolled, single center, open-label study with an adaptive design conducted in two cohorts: Ascending Dose (AD) cohort and Therapeutic Dose (TD) cohort.
primary purpose: Treatment
masking: None (Open Label)
measure: Safety of the treatment with LIS1: Blood pressure
time frame: up to 3 months after the transplant
description: Clinical safety parameters (1): Systolic and diastolic blood pressure (mm Hg).
measure: Safety of the treatment with LIS1: Pulse rate
time frame: up to 3 months after the transplant
description: Clinical safety parameters (2): Pulse rate (beats per minute [bpm]) .
measure: Safety of the treatment with LIS1: Body temperature
time frame: up to 3 months after the transplant
description: Clinical safety parameters (3): Body temperature (Celsius degrees).
measure: Safety of the treatment with LIS1: Graft rejection
time frame: up to 3 months after the transplant
description: Clinical safety parameters (4): Graft rejection (yes/no).
measure: Safety of the treatment with LIS1: Infection
time frame: up to 3 months after the transplant
description: Clinical safety parameters (5): Viral infections (namely Cytomegalovirus [CMV], BK virus) (yes/no).
measure: Safety of the treatment with LIS1: Re-admission
time frame: up to 3 months after the transplant
description: Clinical safety parameters (6): Re-admission after patient discharge (yes/no).
measure: Safety of the treatment with LIS1: Hospitalization
time frame: up to 3 months after the transplant
description: Clinical safety parameters (7): Prolonged stay in hospital for >4 weeks (days).
measure: Safety of the treatment with LIS1: CRP
time frame: up to 3 months after the transplant
description: Laboratory parameters (1): C-Reactive Protein (CRP, mg/L).
measure: Safety of the treatment with LIS1: LDH
time frame: up to 3 months after the transplant
description: Laboratory parameters (2): Lactate Dehydrogenase (LDH, µkat/L).
measure: Safety of the treatment with LIS1: aPTT
time frame: up to 3 months after the transplant
description: Laboratory parameters (3): activated Partial Thromboplastin Time (aPTT, seconds).
measure: Safety of the treatment with LIS1: Complete Blood Count (CBC)
time frame: up to 3 months after the transplant
description: Laboratory parameters (4): Platelets (10^9/L), white blood cells (10^9/L), absolute neutrophil count (10^9/L), absolute lymphocyte count (10^9/L), absolute monocyte count (10^9/L), absolute eosinophil count (10^9/L), absolute basophil count (10^9/L).
measure: Pharmacodynamics (depletion of T lymphocytes) of LIS1
time frame: up to 3 months after the transplant
description: Absolute T lymphocyte counts (10^9/L).
measure: Pharmacokinetics of LIS1 (1): swine IgG
time frame: up to 3 months after the transplant
description: Serum concentration of swine IgG
measure: Pharmacodynamics of LIS1 (2): cytokines
time frame: up to 3 months after the transplant
description: Cytokine concentration (IL6, TNFα) (ng/mL).
measure: Biology of LIS1 (1): electrolytes plasma concentration
time frame: up to 3 months after the transplant
description: Plasma biochemistry: electrolytes (Na+, K+, Cl-, Ca++, Mg++, bicarbonates plasma concentrations mmol/L)
measure: Biology of LIS1 (2): urea and creatinine
time frame: up to 3 months after the transplant
description: Plasma biochemistry: urea and creatinine plasma concentration (mmol/L)
measure: Biology of LIS1 (3): total plasma proteins
time frame: up to 3 months after the transplant
description: Plasma biochemistry: Total protein plasma concentration (g/L)
measure: Biology of LIS1 (4): plasmatic proteins
time frame: up to 3 months after the transplant
description: Plasma biochemistry: electrophoresis of plasmatic proteins (percentages of albumin, alpha-1-globulin, alpha-2-globulin, beta-globulin, gamma-globulin)
measure: Immunogenicity of LIS1
time frame: up to 3 months after the transplant
description: Detection of antidrug antibodies in serum
arm group label: Ascending Dose Cohort
arm group type: Experimental
description: The AD cohort will be first recruited and will include 5 patients: 1 patient per dose, sequentially recruited, the recruitment of the next dose level patient will be assessed by Data Safety Monitoring Board :
Patient 1: 0.6 mg/Kg/day
Patient 2: 1 mg/Kg/day
Patient 3: 3 mg/Kg/day
Patient 4: 6 mg/Kg/day
Patient 5: 8 mg/Kg/day
Once the 5 AD patients complete LIS1 treatment, the sponsor and the DSMB will rule on the LIS1 dose to obtain an optimal CD3+ cells depletion, with a good safety profile and will determine the therapeutic dose.
arm group label: Therapeutic Dose Cohort
arm group type: Experimental
description: The TD cohort will be recruited once the therapeutic dose is defined. This cohort will be divided in 2 subgroups of respectively 2 and 3 patients sequentially recruited.
DSMB will review the safety and efficacy profile of the first 2 patients (Subgroup1) and decide:
To continue at the same dose and recruit the next 3 patients of Subgroup 2
To recruit the next 3 patients with a lower dose, estimated from AD as bringing efficient depletion
To recruit the next patient with a higher dose (+2 mg/kg), if the depletion is not considered satisfactory and if the safety profile is considered acceptable
To end the trial if LIS1 toxicity is too important vs its efficacy in CD3+ depletion.
If the decision to increase the dose after the first two TD patients is made, an additional DSMB review will be planned after patient 8. The DSMB will decide to maintain the dose for the last 2 patients or to get back to the previous dose
intervention type: Biological
intervention name: LIS1
description: LIS1 is an induction treatment on top of maintenance immunosuppressive regimen. All patients from AD and TD cohort will receive the conventional immunosuppressive regimen: tacrolimus (0.2 mg/kg) / mycophenolic acid (MMF, 2x1000 mg) / prednisone (20 mg from day 2). This conventional treatment should be started and monitored for all patients independently of their participation in the clinical trial. Methylprednisolone 500 mg / 100 mL saline / 30 minutes will be administered before reperfusion during the surgery and on post operation day 1 just before LIS1 administration.
arm group label: Ascending Dose Cohort
arm group label: Therapeutic Dose Cohort
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: No
last name: Dr Ondrej Viklicky
role: Principal Investigator
affiliation: Institut klinické a experimentální medicíny, Praha 4, Czech Republic
facility: 
country: Czechia
responsible party type: Sponsor