<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/NCT03776786</url>
  </required_header>
  <id_info>
    <org_study_id>YFT-001</org_study_id>
    <secondary_id>CTA1800118</secondary_id>
    <nct_id>NCT03776786</nct_id>
  </id_info>
  <brief_title>Safety and Tolerability of an Antibody Against Yellow Fever Virus (TY014) in Humans</brief_title>
  <official_title>Phase 1 First-in-Human, Time Lagged, Single Ascending Dose Study of TY014 in Healthy Adult Volunteers (Safety Arm - 1A) and Sequential Time Lagged, Parallel-Group, Randomised, Placebo-Controlled, Double-Blind, Single Ascending Dose Study of TY014 in YF-17D Vaccine Strain-Challenged Healthy Adult Volunteers (Efficacy Arm - 1B)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Tysana Pte Ltd</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Tysana Pte Ltd</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>
      Yellow Fever is an acute viral hemorrhagic disease caused by the Yellow Fever Virus (YFV), a&#xD;
      re-emerging arbovirus transmitted by the same mosquito vector (Aedes aegypti) that transmits&#xD;
      Dengue virus (DENV) and Zika virus (ZIKV). YFV is endemic in tropical and subtropical areas&#xD;
      of South America and Africa, causing an estimated 200,000 infections and 30,000 deaths&#xD;
      annually. It has now become a growing public health problem, rapidly spreading throughout the&#xD;
      two (2) continents in a cyclical pattern. With climate change, global travel and&#xD;
      urbanisation, which increase the chance for mosquito-borne diseases to spread rapidly, the&#xD;
      risk of YFV establishing its foothold in the Asia-Pacific region with periodic epidemic&#xD;
      bursts remains a real public health concern.&#xD;
&#xD;
      Although there is currently a safe and effective vaccine available on the market, global&#xD;
      shortages of supplies have severely hampered any efforts in the prevention and control of YFV&#xD;
      outbreaks. To date, no YFV therapy (biologic or small molecule) has advanced to clinical&#xD;
      trials. TY014 will be the first therapeutic in the world, specifically targeting YFV, to&#xD;
      enter clinical trials. It is anticipated that a monoclonal antibody therapeutic could be&#xD;
      administered to infected cases to reduce disease severity within the patient and their&#xD;
      contacts.&#xD;
&#xD;
      This is a Phase 1, first-in-human TY014, YFV monoclonal antibody (mAb), study to be conducted&#xD;
      in two (2) arms:&#xD;
&#xD;
        -  Safety Arm (1A): Healthy adult volunteers&#xD;
&#xD;
        -  Efficacy Arm (1B): Healthy adult volunteers challenged with YF-17D Vaccine Strain 24&#xD;
           hours prior to TY014 dosing&#xD;
&#xD;
      TY014 will be administered once through single IV infusion over 30 minutes. Total duration of&#xD;
      study participation is estimated at approximately 114 days from the date of screening.&#xD;
&#xD;
      The main objectives of this study are to: (a) evaluate the safety of TY014 in healthy adult&#xD;
      volunteers, and (b) evaluate the safety of TY014 in YF-17D Vaccine Strain-challenged healthy&#xD;
      adult volunteers. Percentage aviremia of YF-17D Vaccine Strain-challenged subjects within 48&#xD;
      hours after IV infusion of TY014 will also be assessed.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Safety Arm (1A):&#xD;
&#xD;
      Safety Arm is a phase 1A First-in-Human, Time Lagged, Single Ascending Dose Study of TY014 in&#xD;
      Healthy Adult Volunteers.&#xD;
&#xD;
      Safety, tolerability and PK of TY014 will be assessed. The dose escalation will include 27&#xD;
      healthy volunteers in five (5) dose cohorts:&#xD;
&#xD;
        -  0.5 mg/kg, N = 2 TY014 + 5 Placebos&#xD;
&#xD;
        -  2 mg/kg, N = 5 TY014&#xD;
&#xD;
        -  5 mg/kg, N = 5 TY014&#xD;
&#xD;
        -  10 mg/kg, N = 5 TY014&#xD;
&#xD;
        -  20 mg/kg, N = 5 TY014 Subjects will be required to be inpatient at the trial site for&#xD;
           approximately 72 hours.&#xD;
&#xD;
      Dose escalations will be guided by a safety review of clinical signs, adverse events (AEs),&#xD;
      and laboratory tests (excluding lipase) of the prior group (up to 48 hours post-dose for&#xD;
      cohort 1, and up to Day 7 post-dose for cohorts 2 - 5).&#xD;
&#xD;
      A minimum of 20-hour interval from the first TY014 treatment subject dosing must take place&#xD;
      before the second TY014 treatment subject can be dosed within each cohort. No such time&#xD;
      interval will be required for dosing of subsequent TY014 treatment subjects (third subject&#xD;
      onwards) within the same cohort, as well as Placebo dosing in dose cohort 1 (i.e. all five&#xD;
      placebos can be dosed at the same time).&#xD;
&#xD;
      After 72 hours, subjects will be discharged from trial site and to return for scheduled&#xD;
      follow-up visits.&#xD;
&#xD;
      Subjects will be followed for up to approximately Day 84 for PK sampling, with serum samples&#xD;
      taken at specified times.&#xD;
&#xD;
      Dose escalations for the Safety (1A) Arm will be guided by a safety review of clinical signs,&#xD;
      adverse events (AEs), and laboratory tests (excluding lipase) of the prior dose cohort (up to&#xD;
      Day 7).&#xD;
&#xD;
      Similar safety review (up to Day 7) will also be completed for the equivalent dose in Safety&#xD;
      Arm (1A) prior to the commencement of the Efficacy Arm (1B) for each specified dose.&#xD;
&#xD;
      Efficacy Arm (1B):&#xD;
&#xD;
      Efficacy Arm is a phase 1B Sequential Time Lagged, Parallel-Group, Randomised,&#xD;
      Placebo-Controlled, Double-Blind, Single Ascending Dose Study of TY014 in YF-17D Vaccine&#xD;
      Strain-Challenged Healthy Adult Volunteers.&#xD;
&#xD;
      Safety, tolerability and time to achieve aviremia through negative YFV isolation from blood&#xD;
      in YF-17D Vaccine Strain-challenged healthy adult volunteers when given an IV infusion of&#xD;
      TY014 will be assessed.&#xD;
&#xD;
      Eligible subjects will be randomised into TY014 or Placebo Group in each cohort.&#xD;
&#xD;
      The dose escalation will include up to 40 healthy volunteers in up to four (4) dose cohorts:&#xD;
&#xD;
        -  2 mg/kg, N = 5 TY014 + 5 Placebos&#xD;
&#xD;
        -  5 mg/kg, N = 5 TY014 + 5 Placebos&#xD;
&#xD;
        -  10 mg/kg, N = 5 TY014 + 5 Placebos&#xD;
&#xD;
        -  20 mg/kg, N = 5 TY014 + 5 Placebos Efficacy Arm (1B) will be based on an adaptive trial&#xD;
           design, with ten (10) YF-17D vaccinated subjects from each dose cohort being randomised&#xD;
           1:1 into either TY014 or Placebo group, five (5) subjects in each group. After TY014 or&#xD;
           placebo administration, safety and efficacy of TY014 in YF-17D Vaccine Strain-Challenged&#xD;
           subjects will be assessed.&#xD;
&#xD;
           i) If current dose of TY014 shows safety but not efficacy*, Efficacy Arm (1B) will&#xD;
           escalate to the next dose cohort.&#xD;
&#xD;
      ii) If current dose of TY014 is safe and efficacious*, efficacious dose of TY014 is&#xD;
      established and the Efficacy Arm (1B) of the trial is completed.&#xD;
&#xD;
      *Efficacy of TY014 is defined as aviremia by virus isolation being observed in 100% of&#xD;
      vaccinated subjects within 48 hours post-dosing.&#xD;
&#xD;
      Subjects will be required to be inpatient at the trial site for approximately 96 hours.&#xD;
&#xD;
      Subjects will be vaccinated with the YF-17D Vaccine on Day -1. On Day 0, 24 hours after&#xD;
      vaccination, subjects will then be administered TY014 or Placebo.&#xD;
&#xD;
      A minimum of 20-hour interval from the first two (2) subjects dosing (1 treatment and 1&#xD;
      placebo concurrently) must take place before the third subject can be dosed within each&#xD;
      cohort. No such time interval will be required for dosing of subsequent subjects (fourth&#xD;
      subject onwards) within the same cohort.&#xD;
&#xD;
      After 96 hours, subjects will be discharged from trial site and are to return for scheduled&#xD;
      follow-up visits.&#xD;
&#xD;
      PD and PK measurements will be conducted at various time points throughout the study.&#xD;
      Subjects will be followed for up to approximately Day 84 post-dose. Samples for PD (serum and&#xD;
      urine) and PK (serum) assessments will be taken at specified time points.&#xD;
&#xD;
      Dose escalations for the Efficacy (1B) Arm will be guided by a safety review of clinical&#xD;
      signs, adverse events (AEs), laboratory tests (excluding lipase) and presence of viremia (via&#xD;
      virus isolation) of the prior dose cohort (up to Day 14). Escalation to the next dose cohort&#xD;
      (e.g. from dose cohort 1 (2 mg/kg) to dose cohort 2 (5 mg/kg), from dose cohort 2 (5 mg/kg)&#xD;
      to dose cohort 3 (10 mg/kg) and from dose cohort 3 (10 mg/kg) to dose cohort 4 (20 mg/kg))&#xD;
      will only be conducted if from prior dose cohort (e.g. dose cohort 1 (2 mg/kg), dose cohort 2&#xD;
      (5 mg/kg) and dose cohort 3 (10 mg/kg) respectively):&#xD;
&#xD;
        1. safety (up to Day 14 post-dose) has been established through a safety review, and&#xD;
&#xD;
        2. presence of viremia (up to 48 hours post-dose) via virus isolation in any of the&#xD;
           TY014-treated subjects.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 6, 2018</start_date>
  <completion_date type="Actual">October 10, 2019</completion_date>
  <primary_completion_date type="Actual">July 1, 2019</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence of Treatment-Emergent Adverse Event (Safety and Tolerability)</measure>
    <time_frame>84 Days</time_frame>
    <description>Presence or absence of infusion reaction (hypersensitivity / anaphylaxis / etc.) in dose cohorts.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Percentage Aviremia Post Treatment (Efficacy Arm only)</measure>
    <time_frame>14 Days</time_frame>
    <description>Percentage of YF-17D Vaccine Strain-challenged healthy adult volunteers showing aviremia via virus isolation within 48 hours after given an IV infusion of TY014</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maximum Concentration (Cmax) - Pharmacokinetic Assessment</measure>
    <time_frame>84 Days</time_frame>
    <description>Constant monitoring of the levels of antibody in subject sera through various time points as stated below would help elucidate the maximum concentration (Cmax) of TY014 in human serum.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Maximum Concentration (Tmax) - Pharmacokinetic Assessment</measure>
    <time_frame>84 Days</time_frame>
    <description>Constant monitoring of the levels of antibody in subject sera through various time points as stated below would help elucidate the time to maximum concentration (Tmax) of TY014 in human serum.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area Under the Curve Extrapolated to Infinity (AUC0-∞) - Pharmacokinetic Assessment</measure>
    <time_frame>84 Days</time_frame>
    <description>Constant monitoring of the levels of antibody in subject sera through various time points as stated below would help elucidate the area under the curve extrapolated to infinity (AUC0-∞) of TY014.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC calculated from time of administration to the last measurable concentration (AUC0-last) - Pharmacokinetic Assessment</measure>
    <time_frame>84 Days</time_frame>
    <description>Constant monitoring of the levels of antibody in subject sera through various time points as stated below would help elucidate the AUC calculated from time of administration to the last measurable concentration (AUC0-last) of TY014.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Half-Life (t1/2) - Pharmacokinetic Assessment</measure>
    <time_frame>84 Days</time_frame>
    <description>Constant monitoring of the levels of antibody in subject sera through various time points as stated below would help elucidate the half-life (t1/2) of TY014 in human serum.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Volume of Distribution (Vd) - Pharmacokinetic Assessment</measure>
    <time_frame>84 Days</time_frame>
    <description>Constant monitoring of the levels of antibody in subject sera through various time points as stated below would help elucidate the volume of distribution (Vd) of TY014 in human serum.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clearance [CL] - Pharmacokinetic Assessment</measure>
    <time_frame>84 Days</time_frame>
    <description>Constant monitoring of the levels of antibody in subject sera through various time points as stated below would help elucidate clearance [CL] of TY014 in human serum.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Viral Load Reduction (Efficacy Arm only)</measure>
    <time_frame>84 Days</time_frame>
    <description>Assess YFV viral load reduction from blood by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) in YF-17D Vaccine Strain-challenged healthy adult volunteers when given an IV infusion of TY014.</description>
  </secondary_outcome>
  <number_of_arms>14</number_of_arms>
  <enrollment type="Actual">37</enrollment>
  <condition>Treatment of Acute Yellow Fever Virus Infection</condition>
  <arm_group>
    <arm_group_label>Safety Arm - 0.5 mg/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subject will be administered with 0.5 mg/kg of TY014 via IV infusion over a period of 30 minutes.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Safety Arm - Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subject will be administered with 0.9% saline via IV infusion over a period of 30 minutes.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Safety Arm - 2 mg/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subject will be administered with 2 mg/kg of TY014 via IV infusion over a period of 30 minutes.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Safety Arm - 5 mg/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subject will be administered with 5 mg/kg of TY014 via IV infusion over a period of 30 minutes.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Safety Arm - 10 mg/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subject will be administered with 10 mg/kg of TY014 via IV infusion over a period of 30 minutes.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Safety Arm - 20 mg/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subject will be administered with 20 mg/kg of TY014 via IV infusion over a period of 30 minutes.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Efficacy Arm - 2 mg/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subject will be administered with 2 mg/kg of TY014 via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Efficacy Arm - 2 mg/kg Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subject will be administered with 0.9% saline via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Efficacy Arm - 5 mg/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subject will be administered with 5 mg/kg of TY014 via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Efficacy Arm - 5 mg/kg Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subject will be administered with 0.9% saline via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Efficacy Arm - 10 mg/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subject will be administered with 10 mg/kg of TY014 via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Efficacy Arm - 10 mg/kg Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subject will be administered with 0.9% saline via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Efficacy Arm - 20 mg/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subject will be administered with 20 mg/kg of TY014 via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Efficacy Arm - 20 mg/kg Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subject will be administered with 0.9% saline via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>TY014</intervention_name>
    <description>TY014 Injection, (100 mg/5 mL/Vial), Yellow Fever Virus (YFV) Monoclonal Antibody (mAb)</description>
    <arm_group_label>Efficacy Arm - 10 mg/kg</arm_group_label>
    <arm_group_label>Efficacy Arm - 2 mg/kg</arm_group_label>
    <arm_group_label>Efficacy Arm - 20 mg/kg</arm_group_label>
    <arm_group_label>Efficacy Arm - 5 mg/kg</arm_group_label>
    <arm_group_label>Safety Arm - 0.5 mg/kg</arm_group_label>
    <arm_group_label>Safety Arm - 10 mg/kg</arm_group_label>
    <arm_group_label>Safety Arm - 2 mg/kg</arm_group_label>
    <arm_group_label>Safety Arm - 20 mg/kg</arm_group_label>
    <arm_group_label>Safety Arm - 5 mg/kg</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>0.9% Saline</intervention_name>
    <description>Placebo</description>
    <arm_group_label>Efficacy Arm - 10 mg/kg Placebo</arm_group_label>
    <arm_group_label>Efficacy Arm - 2 mg/kg Placebo</arm_group_label>
    <arm_group_label>Efficacy Arm - 20 mg/kg Placebo</arm_group_label>
    <arm_group_label>Efficacy Arm - 5 mg/kg Placebo</arm_group_label>
    <arm_group_label>Safety Arm - Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Healthy adult volunteers, aged 21 to 50 years old, men or women&#xD;
&#xD;
          2. Subjects negative for human immunodeficiency virus (HIV), Hepatitis B virus surface&#xD;
             Antigen (HBsAg) and Hepatitis C virus (HCV)&#xD;
&#xD;
          3. Subjects who have not been vaccinated against or had prior exposure to Yellow Fever&#xD;
             Virus (YFV)&#xD;
&#xD;
          4. Subjects who have no history of travels to Central America, South America, Africa or&#xD;
             any other YF endemic countries, and have no plans to visit Central America, South&#xD;
             America, Africa or any other YF endemic countries in the next six (6) months&#xD;
&#xD;
          5. Subjects who are willing to comply with the requirements of the study protocol, attend&#xD;
             scheduled visits and make themselves available for the duration of the study with&#xD;
             access to a consistent means of telephone contact, which may be, but not limited to,&#xD;
             at home or at work via landline or mobile&#xD;
&#xD;
          6. Subjects who give written informed consent approved by the Ethical Review Board&#xD;
             governing the site&#xD;
&#xD;
          7. Satisfactory baseline medical assessment as assessed by physical examination and a&#xD;
             stable health status. Normal laboratory values must be within normal range of the&#xD;
             assessing site or show minor variations that are deemed not clinically significant as&#xD;
             judged by the Investigator and acceptable for study entry. A stable health status is&#xD;
             defined as the absence of a health event satisfying the definition of a serious&#xD;
             adverse event&#xD;
&#xD;
          8. Accessible vein in the forearm for blood collection&#xD;
&#xD;
          9. Female subjects of childbearing potential may be enrolled in the study if they have&#xD;
             negative urine pregnancy tests on the day of screening and day of admission&#xD;
&#xD;
         10. Female subjects of non-childbearing potential due to surgical sterilization&#xD;
             (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause.&#xD;
             Post-menopause subjects must have had at least 12 months of natural (spontaneous)&#xD;
             amenorrhea&#xD;
&#xD;
         11. Both male (if he has a partner of childbearing potential) and female subjects (of&#xD;
             childbearing potential) must agree to use adequate and reliable contraceptive measures&#xD;
             (e.g. spermicides, condoms, contraceptive pills, etc.) or practice abstinence&#xD;
             throughout the duration of the study (up to 84 days post-dosing)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Presence of acute infection in the preceding 14 days, or presence of a temperature ≥&#xD;
             38.0 ˚C (oral or tympanic temperature assessment), or acute symptoms greater than of&#xD;
             &quot;mild&quot; severity on the scheduled date of admission&#xD;
&#xD;
          2. History of severe drug and / or food allergies and / or known allergies to the trial&#xD;
             product or its components&#xD;
&#xD;
          3. Female subject who is pregnant or breast-feeding&#xD;
&#xD;
          4. History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal,&#xD;
             neuropsychiatric, or immunosuppressive disorders&#xD;
&#xD;
          5. Evidence of clinically significant anaemia (HB &lt; 10 g/dL) or any other significant&#xD;
             active haematological disease, or having donated &gt; 450 mL of blood within the past&#xD;
             three (3) months&#xD;
&#xD;
          6. Evidence of substance abuse, or previous substance abuse&#xD;
&#xD;
          7. Participation or planned participation in a study involving the administration of an&#xD;
             investigational compound within the past four (4) months or during this study period&#xD;
&#xD;
          8. Receipt of immunoglobulins and/or any blood products within nine (9) months of study&#xD;
             enrolment or planned administration of any of these products during the study period&#xD;
&#xD;
          9. Administration of any licensed vaccine within 30 days before the first study vaccine&#xD;
             dose.&#xD;
&#xD;
         10. History of any reaction to monoclonal antibodies&#xD;
&#xD;
         11. Any condition that, in the opinion of the Investigator, would complicate or compromise&#xD;
             the study or well-being of the subject&#xD;
&#xD;
         12. Both male (if he has a partner of childbearing potential) and female subjects (of&#xD;
             childbearing potential) who are unwilling to use adequate contraception or practice&#xD;
             abstinence throughout the duration of the study (up to 84 days post-dosing)&#xD;
&#xD;
        Efficacy Arm (1B) only:&#xD;
&#xD;
        Subjects meeting any of the following criteria will be excluded from the study:&#xD;
&#xD;
          1. Planned travels to Central America, South America, Africa or any other YFV-endemic&#xD;
             countries in the next six (6) months&#xD;
&#xD;
          2. History of thymus gland disease.&#xD;
&#xD;
          3. Diagnosed with cancer or on treatment for cancer with the three (3) years prior to the&#xD;
             screening.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jenny Low, MBBS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Singapore General Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>SingHealth Investigational Medicine Unit</name>
      <address>
        <city>Singapore</city>
        <zip>169608</zip>
        <country>Singapore</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Singapore</country>
  </location_countries>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>December 12, 2018</study_first_submitted>
  <study_first_submitted_qc>December 12, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 17, 2018</study_first_posted>
  <last_update_submitted>October 24, 2019</last_update_submitted>
  <last_update_submitted_qc>October 24, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">October 25, 2019</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>Yellow Fever</mesh_term>
    <mesh_term>Fever</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03776786
org study id: YFT-001
secondary id: CTA1800118
nct id: NCT03776786
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Yellow Fever is an acute viral hemorrhagic disease caused by the Yellow Fever Virus (YFV), a
      re-emerging arbovirus transmitted by the same mosquito vector (Aedes aegypti) that transmits
      Dengue virus (DENV) and Zika virus (ZIKV). YFV is endemic in tropical and subtropical areas
      of South America and Africa, causing an estimated 200,000 infections and 30,000 deaths
      annually. It has now become a growing public health problem, rapidly spreading throughout the
      two (2) continents in a cyclical pattern. With climate change, global travel and
      urbanisation, which increase the chance for mosquito-borne diseases to spread rapidly, the
      risk of YFV establishing its foothold in the Asia-Pacific region with periodic epidemic
      bursts remains a real public health concern.

      Although there is currently a safe and effective vaccine available on the market, global
      shortages of supplies have severely hampered any efforts in the prevention and control of YFV
      outbreaks. To date, no YFV therapy (biologic or small molecule) has advanced to clinical
      trials. TY014 will be the first therapeutic in the world, specifically targeting YFV, to
      enter clinical trials. It is anticipated that a monoclonal antibody therapeutic could be
      administered to infected cases to reduce disease severity within the patient and their
      contacts.

      This is a Phase 1, first-in-human TY014, YFV monoclonal antibody (mAb), study to be conducted
      in two (2) arms:

        -  Safety Arm (1A): Healthy adult volunteers

        -  Efficacy Arm (1B): Healthy adult volunteers challenged with YF-17D Vaccine Strain 24
           hours prior to TY014 dosing

      TY014 will be administered once through single IV infusion over 30 minutes. Total duration of
      study participation is estimated at approximately 114 days from the date of screening.

      The main objectives of this study are to: (a) evaluate the safety of TY014 in healthy adult
      volunteers, and (b) evaluate the safety of TY014 in YF-17D Vaccine Strain-challenged healthy
      adult volunteers. Percentage aviremia of YF-17D Vaccine Strain-challenged subjects within 48
      hours after IV infusion of TY014 will also be assessed.
Safety Arm (1A):

      Safety Arm is a phase 1A First-in-Human, Time Lagged, Single Ascending Dose Study of TY014 in
      Healthy Adult Volunteers.

      Safety, tolerability and PK of TY014 will be assessed. The dose escalation will include 27
      healthy volunteers in five (5) dose cohorts:

        -  0.5 mg/kg, N = 2 TY014 + 5 Placebos

        -  2 mg/kg, N = 5 TY014

        -  5 mg/kg, N = 5 TY014

        -  10 mg/kg, N = 5 TY014

        -  20 mg/kg, N = 5 TY014 Subjects will be required to be inpatient at the trial site for
           approximately 72 hours.

      Dose escalations will be guided by a safety review of clinical signs, adverse events (AEs),
      and laboratory tests (excluding lipase) of the prior group (up to 48 hours post-dose for
      cohort 1, and up to Day 7 post-dose for cohorts 2 - 5).

      A minimum of 20-hour interval from the first TY014 treatment subject dosing must take place
      before the second TY014 treatment subject can be dosed within each cohort. No such time
      interval will be required for dosing of subsequent TY014 treatment subjects (third subject
      onwards) within the same cohort, as well as Placebo dosing in dose cohort 1 (i.e. all five
      placebos can be dosed at the same time).

      After 72 hours, subjects will be discharged from trial site and to return for scheduled
      follow-up visits.

      Subjects will be followed for up to approximately Day 84 for PK sampling, with serum samples
      taken at specified times.

      Dose escalations for the Safety (1A) Arm will be guided by a safety review of clinical signs,
      adverse events (AEs), and laboratory tests (excluding lipase) of the prior dose cohort (up to
      Day 7).

      Similar safety review (up to Day 7) will also be completed for the equivalent dose in Safety
      Arm (1A) prior to the commencement of the Efficacy Arm (1B) for each specified dose.

      Efficacy Arm (1B):

      Efficacy Arm is a phase 1B Sequential Time Lagged, Parallel-Group, Randomised,
      Placebo-Controlled, Double-Blind, Single Ascending Dose Study of TY014 in YF-17D Vaccine
      Strain-Challenged Healthy Adult Volunteers.

      Safety, tolerability and time to achieve aviremia through negative YFV isolation from blood
      in YF-17D Vaccine Strain-challenged healthy adult volunteers when given an IV infusion of
      TY014 will be assessed.

      Eligible subjects will be randomised into TY014 or Placebo Group in each cohort.

      The dose escalation will include up to 40 healthy volunteers in up to four (4) dose cohorts:

        -  2 mg/kg, N = 5 TY014 + 5 Placebos

        -  5 mg/kg, N = 5 TY014 + 5 Placebos

        -  10 mg/kg, N = 5 TY014 + 5 Placebos

        -  20 mg/kg, N = 5 TY014 + 5 Placebos Efficacy Arm (1B) will be based on an adaptive trial
           design, with ten (10) YF-17D vaccinated subjects from each dose cohort being randomised
           1:1 into either TY014 or Placebo group, five (5) subjects in each group. After TY014 or
           placebo administration, safety and efficacy of TY014 in YF-17D Vaccine Strain-Challenged
           subjects will be assessed.

           i) If current dose of TY014 shows safety but not efficacy*, Efficacy Arm (1B) will
           escalate to the next dose cohort.

      ii) If current dose of TY014 is safe and efficacious*, efficacious dose of TY014 is
      established and the Efficacy Arm (1B) of the trial is completed.

      *Efficacy of TY014 is defined as aviremia by virus isolation being observed in 100% of
      vaccinated subjects within 48 hours post-dosing.

      Subjects will be required to be inpatient at the trial site for approximately 96 hours.

      Subjects will be vaccinated with the YF-17D Vaccine on Day -1. On Day 0, 24 hours after
      vaccination, subjects will then be administered TY014 or Placebo.

      A minimum of 20-hour interval from the first two (2) subjects dosing (1 treatment and 1
      placebo concurrently) must take place before the third subject can be dosed within each
      cohort. No such time interval will be required for dosing of subsequent subjects (fourth
      subject onwards) within the same cohort.

      After 96 hours, subjects will be discharged from trial site and are to return for scheduled
      follow-up visits.

      PD and PK measurements will be conducted at various time points throughout the study.
      Subjects will be followed for up to approximately Day 84 post-dose. Samples for PD (serum and
      urine) and PK (serum) assessments will be taken at specified time points.

      Dose escalations for the Efficacy (1B) Arm will be guided by a safety review of clinical
      signs, adverse events (AEs), laboratory tests (excluding lipase) and presence of viremia (via
      virus isolation) of the prior dose cohort (up to Day 14). Escalation to the next dose cohort
      (e.g. from dose cohort 1 (2 mg/kg) to dose cohort 2 (5 mg/kg), from dose cohort 2 (5 mg/kg)
      to dose cohort 3 (10 mg/kg) and from dose cohort 3 (10 mg/kg) to dose cohort 4 (20 mg/kg))
      will only be conducted if from prior dose cohort (e.g. dose cohort 1 (2 mg/kg), dose cohort 2
      (5 mg/kg) and dose cohort 3 (10 mg/kg) respectively):

        1. safety (up to Day 14 post-dose) has been established through a safety review, and

        2. presence of viremia (up to 48 hours post-dose) via virus isolation in any of the
           TY014-treated subjects.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Incidence of Treatment-Emergent Adverse Event (Safety and Tolerability)
time frame: 84 Days
description: Presence or absence of infusion reaction (hypersensitivity / anaphylaxis / etc.) in dose cohorts.
measure: Percentage Aviremia Post Treatment (Efficacy Arm only)
time frame: 14 Days
description: Percentage of YF-17D Vaccine Strain-challenged healthy adult volunteers showing aviremia via virus isolation within 48 hours after given an IV infusion of TY014
measure: Maximum Concentration (Cmax) - Pharmacokinetic Assessment
time frame: 84 Days
description: Constant monitoring of the levels of antibody in subject sera through various time points as stated below would help elucidate the maximum concentration (Cmax) of TY014 in human serum.
measure: Time to Maximum Concentration (Tmax) - Pharmacokinetic Assessment
time frame: 84 Days
description: Constant monitoring of the levels of antibody in subject sera through various time points as stated below would help elucidate the time to maximum concentration (Tmax) of TY014 in human serum.
measure: Area Under the Curve Extrapolated to Infinity (AUC0-∞) - Pharmacokinetic Assessment
time frame: 84 Days
description: Constant monitoring of the levels of antibody in subject sera through various time points as stated below would help elucidate the area under the curve extrapolated to infinity (AUC0-∞) of TY014.
measure: AUC calculated from time of administration to the last measurable concentration (AUC0-last) - Pharmacokinetic Assessment
time frame: 84 Days
description: Constant monitoring of the levels of antibody in subject sera through various time points as stated below would help elucidate the AUC calculated from time of administration to the last measurable concentration (AUC0-last) of TY014.
measure: Half-Life (t1/2) - Pharmacokinetic Assessment
time frame: 84 Days
description: Constant monitoring of the levels of antibody in subject sera through various time points as stated below would help elucidate the half-life (t1/2) of TY014 in human serum.
measure: Volume of Distribution (Vd) - Pharmacokinetic Assessment
time frame: 84 Days
description: Constant monitoring of the levels of antibody in subject sera through various time points as stated below would help elucidate the volume of distribution (Vd) of TY014 in human serum.
measure: Clearance [CL] - Pharmacokinetic Assessment
time frame: 84 Days
description: Constant monitoring of the levels of antibody in subject sera through various time points as stated below would help elucidate clearance [CL] of TY014 in human serum.
measure: Viral Load Reduction (Efficacy Arm only)
time frame: 84 Days
description: Assess YFV viral load reduction from blood by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) in YF-17D Vaccine Strain-challenged healthy adult volunteers when given an IV infusion of TY014.
arm group label: Safety Arm - 0.5 mg/kg
arm group type: Experimental
description: Subject will be administered with 0.5 mg/kg of TY014 via IV infusion over a period of 30 minutes.
arm group label: Safety Arm - Placebo
arm group type: Placebo Comparator
description: Subject will be administered with 0.9% saline via IV infusion over a period of 30 minutes.
arm group label: Safety Arm - 2 mg/kg
arm group type: Experimental
description: Subject will be administered with 2 mg/kg of TY014 via IV infusion over a period of 30 minutes.
arm group label: Safety Arm - 5 mg/kg
arm group type: Experimental
description: Subject will be administered with 5 mg/kg of TY014 via IV infusion over a period of 30 minutes.
arm group label: Safety Arm - 10 mg/kg
arm group type: Experimental
description: Subject will be administered with 10 mg/kg of TY014 via IV infusion over a period of 30 minutes.
arm group label: Safety Arm - 20 mg/kg
arm group type: Experimental
description: Subject will be administered with 20 mg/kg of TY014 via IV infusion over a period of 30 minutes.
arm group label: Efficacy Arm - 2 mg/kg
arm group type: Experimental
description: Subject will be administered with 2 mg/kg of TY014 via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.
arm group label: Efficacy Arm - 2 mg/kg Placebo
arm group type: Placebo Comparator
description: Subject will be administered with 0.9% saline via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.
arm group label: Efficacy Arm - 5 mg/kg
arm group type: Experimental
description: Subject will be administered with 5 mg/kg of TY014 via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.
arm group label: Efficacy Arm - 5 mg/kg Placebo
arm group type: Placebo Comparator
description: Subject will be administered with 0.9% saline via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.
arm group label: Efficacy Arm - 10 mg/kg
arm group type: Experimental
description: Subject will be administered with 10 mg/kg of TY014 via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.
arm group label: Efficacy Arm - 10 mg/kg Placebo
arm group type: Placebo Comparator
description: Subject will be administered with 0.9% saline via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.
arm group label: Efficacy Arm - 20 mg/kg
arm group type: Experimental
description: Subject will be administered with 20 mg/kg of TY014 via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.
arm group label: Efficacy Arm - 20 mg/kg Placebo
arm group type: Placebo Comparator
description: Subject will be administered with 0.9% saline via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.
intervention type: Biological
intervention name: TY014
description: TY014 Injection, (100 mg/5 mL/Vial), Yellow Fever Virus (YFV) Monoclonal Antibody (mAb)
arm group label: Efficacy Arm - 10 mg/kg
arm group label: Efficacy Arm - 2 mg/kg
arm group label: Efficacy Arm - 20 mg/kg
arm group label: Efficacy Arm - 5 mg/kg
arm group label: Safety Arm - 0.5 mg/kg
arm group label: Safety Arm - 10 mg/kg
arm group label: Safety Arm - 2 mg/kg
arm group label: Safety Arm - 20 mg/kg
arm group label: Safety Arm - 5 mg/kg
intervention type: Other
intervention name: 0.9% Saline
description: Placebo
arm group label: Efficacy Arm - 10 mg/kg Placebo
arm group label: Efficacy Arm - 2 mg/kg Placebo
arm group label: Efficacy Arm - 20 mg/kg Placebo
arm group label: Efficacy Arm - 5 mg/kg Placebo
arm group label: Safety Arm - Placebo
criteria: 
gender: All
minimum age: 21 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Jenny Low, MBBS
role: Principal Investigator
affiliation: Singapore General Hospital
facility: 
country: Singapore
responsible party type: Sponsor
mesh term: Yellow Fever
mesh term: Fever
sharing ipd: No