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Safety and Tolerability of an Antibody Against Yellow Fever Virus (TY014) in Humans

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03776786
Recruitment Status : Completed
First Posted : December 17, 2018
Last Update Posted : October 25, 2019
Sponsor:
Information provided by (Responsible Party):
Tysana Pte Ltd

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Treatment of Acute Yellow Fever Virus Infection Biological: TY014 Other: 0.9% Saline Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 37 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
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)
Actual Study Start Date : December 6, 2018
Actual Primary Completion Date : July 1, 2019
Actual Study Completion Date : October 10, 2019


Arm Intervention/treatment
Experimental: Safety Arm - 0.5 mg/kg
Subject will be administered with 0.5 mg/kg of TY014 via IV infusion over a period of 30 minutes.
Biological: TY014
TY014 Injection, (100 mg/5 mL/Vial), Yellow Fever Virus (YFV) Monoclonal Antibody (mAb)

Placebo Comparator: Safety Arm - Placebo
Subject will be administered with 0.9% saline via IV infusion over a period of 30 minutes.
Other: 0.9% Saline
Placebo

Experimental: Safety Arm - 2 mg/kg
Subject will be administered with 2 mg/kg of TY014 via IV infusion over a period of 30 minutes.
Biological: TY014
TY014 Injection, (100 mg/5 mL/Vial), Yellow Fever Virus (YFV) Monoclonal Antibody (mAb)

Experimental: Safety Arm - 5 mg/kg
Subject will be administered with 5 mg/kg of TY014 via IV infusion over a period of 30 minutes.
Biological: TY014
TY014 Injection, (100 mg/5 mL/Vial), Yellow Fever Virus (YFV) Monoclonal Antibody (mAb)

Experimental: Safety Arm - 10 mg/kg
Subject will be administered with 10 mg/kg of TY014 via IV infusion over a period of 30 minutes.
Biological: TY014
TY014 Injection, (100 mg/5 mL/Vial), Yellow Fever Virus (YFV) Monoclonal Antibody (mAb)

Experimental: Safety Arm - 20 mg/kg
Subject will be administered with 20 mg/kg of TY014 via IV infusion over a period of 30 minutes.
Biological: TY014
TY014 Injection, (100 mg/5 mL/Vial), Yellow Fever Virus (YFV) Monoclonal Antibody (mAb)

Experimental: Efficacy Arm - 2 mg/kg
Subject will be administered with 2 mg/kg of TY014 via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.
Biological: TY014
TY014 Injection, (100 mg/5 mL/Vial), Yellow Fever Virus (YFV) Monoclonal Antibody (mAb)

Placebo Comparator: Efficacy Arm - 2 mg/kg Placebo
Subject will be administered with 0.9% saline via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.
Other: 0.9% Saline
Placebo

Experimental: Efficacy Arm - 5 mg/kg
Subject will be administered with 5 mg/kg of TY014 via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.
Biological: TY014
TY014 Injection, (100 mg/5 mL/Vial), Yellow Fever Virus (YFV) Monoclonal Antibody (mAb)

Placebo Comparator: Efficacy Arm - 5 mg/kg Placebo
Subject will be administered with 0.9% saline via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.
Other: 0.9% Saline
Placebo

Experimental: Efficacy Arm - 10 mg/kg
Subject will be administered with 10 mg/kg of TY014 via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.
Biological: TY014
TY014 Injection, (100 mg/5 mL/Vial), Yellow Fever Virus (YFV) Monoclonal Antibody (mAb)

Placebo Comparator: Efficacy Arm - 10 mg/kg Placebo
Subject will be administered with 0.9% saline via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.
Other: 0.9% Saline
Placebo

Experimental: Efficacy Arm - 20 mg/kg
Subject will be administered with 20 mg/kg of TY014 via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.
Biological: TY014
TY014 Injection, (100 mg/5 mL/Vial), Yellow Fever Virus (YFV) Monoclonal Antibody (mAb)

Placebo Comparator: Efficacy Arm - 20 mg/kg Placebo
Subject will be administered with 0.9% saline via IV infusion over a period of 30 minutes 24 hours post-YF vaccination.
Other: 0.9% Saline
Placebo




Primary Outcome Measures :
  1. Incidence of Treatment-Emergent Adverse Event (Safety and Tolerability) [ Time Frame: 84 Days ]
    Presence or absence of infusion reaction (hypersensitivity / anaphylaxis / etc.) in dose cohorts.

  2. Percentage Aviremia Post Treatment (Efficacy Arm only) [ Time Frame: 14 Days ]
    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


Secondary Outcome Measures :
  1. Maximum Concentration (Cmax) - Pharmacokinetic Assessment [ Time Frame: 84 Days ]
    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.

  2. Time to Maximum Concentration (Tmax) - Pharmacokinetic Assessment [ Time Frame: 84 Days ]
    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.

  3. Area Under the Curve Extrapolated to Infinity (AUC0-∞) - Pharmacokinetic Assessment [ Time Frame: 84 Days ]
    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.

  4. AUC calculated from time of administration to the last measurable concentration (AUC0-last) - Pharmacokinetic Assessment [ Time Frame: 84 Days ]
    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.

  5. Half-Life (t1/2) - Pharmacokinetic Assessment [ Time Frame: 84 Days ]
    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.

  6. Volume of Distribution (Vd) - Pharmacokinetic Assessment [ Time Frame: 84 Days ]
    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.

  7. Clearance [CL] - Pharmacokinetic Assessment [ Time Frame: 84 Days ]
    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.

  8. Viral Load Reduction (Efficacy Arm only) [ Time Frame: 84 Days ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Healthy adult volunteers, aged 21 to 50 years old, men or women
  2. Subjects negative for human immunodeficiency virus (HIV), Hepatitis B virus surface Antigen (HBsAg) and Hepatitis C virus (HCV)
  3. Subjects who have not been vaccinated against or had prior exposure to Yellow Fever Virus (YFV)
  4. Subjects who have no history of travels to Central America, South America, Africa or any other YF endemic countries, and have no plans to visit Central America, South America, Africa or any other YF endemic countries in the next six (6) months
  5. Subjects who are willing to comply with the requirements of the study protocol, attend scheduled visits and make themselves available for the duration of the study with access to a consistent means of telephone contact, which may be, but not limited to, at home or at work via landline or mobile
  6. Subjects who give written informed consent approved by the Ethical Review Board governing the site
  7. Satisfactory baseline medical assessment as assessed by physical examination and a stable health status. Normal laboratory values must be within normal range of the assessing site or show minor variations that are deemed not clinically significant as judged by the Investigator and acceptable for study entry. A stable health status is defined as the absence of a health event satisfying the definition of a serious adverse event
  8. Accessible vein in the forearm for blood collection
  9. Female subjects of childbearing potential may be enrolled in the study if they have negative urine pregnancy tests on the day of screening and day of admission
  10. Female subjects of non-childbearing potential due to surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation) or menopause. Post-menopause subjects must have had at least 12 months of natural (spontaneous) amenorrhea
  11. Both male (if he has a partner of childbearing potential) and female subjects (of childbearing potential) must agree to use adequate and reliable contraceptive measures (e.g. spermicides, condoms, contraceptive pills, etc.) or practice abstinence throughout the duration of the study (up to 84 days post-dosing)

Exclusion Criteria:

  1. Presence of acute infection in the preceding 14 days, or presence of a temperature ≥ 38.0 ˚C (oral or tympanic temperature assessment), or acute symptoms greater than of "mild" severity on the scheduled date of admission
  2. History of severe drug and / or food allergies and / or known allergies to the trial product or its components
  3. Female subject who is pregnant or breast-feeding
  4. History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, neuropsychiatric, or immunosuppressive disorders
  5. Evidence of clinically significant anaemia (HB < 10 g/dL) or any other significant active haematological disease, or having donated > 450 mL of blood within the past three (3) months
  6. Evidence of substance abuse, or previous substance abuse
  7. Participation or planned participation in a study involving the administration of an investigational compound within the past four (4) months or during this study period
  8. Receipt of immunoglobulins and/or any blood products within nine (9) months of study enrolment or planned administration of any of these products during the study period
  9. Administration of any licensed vaccine within 30 days before the first study vaccine dose.
  10. History of any reaction to monoclonal antibodies
  11. Any condition that, in the opinion of the Investigator, would complicate or compromise the study or well-being of the subject
  12. Both male (if he has a partner of childbearing potential) and female subjects (of childbearing potential) who are unwilling to use adequate contraception or practice abstinence throughout the duration of the study (up to 84 days post-dosing)

Efficacy Arm (1B) only:

Subjects meeting any of the following criteria will be excluded from the study:

  1. Planned travels to Central America, South America, Africa or any other YFV-endemic countries in the next six (6) months
  2. History of thymus gland disease.
  3. Diagnosed with cancer or on treatment for cancer with the three (3) years prior to the screening.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03776786


Locations
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Singapore
SingHealth Investigational Medicine Unit
Singapore, Singapore, 169608
Sponsors and Collaborators
Tysana Pte Ltd
Investigators
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Principal Investigator: Jenny Low, MBBS Singapore General Hospital
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Tysana Pte Ltd
ClinicalTrials.gov Identifier: NCT03776786    
Other Study ID Numbers: YFT-001
CTA1800118 ( Other Identifier: Health Sciences Authority of Singapore )
First Posted: December 17, 2018    Key Record Dates
Last Update Posted: October 25, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Yellow Fever
Fever
Body Temperature Changes
Virus Diseases
Infections
Arbovirus Infections
Vector Borne Diseases
Flavivirus Infections
Flaviviridae Infections
RNA Virus Infections
Hemorrhagic Fevers, Viral