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)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 37
- 试验地点
- 2
- 主要终点
- Incidence of Treatment-Emergent Adverse Event (Safety and Tolerability)
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Double (Participant, Investigator)
入排标准
- 年龄范围
- 21 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Healthy adult volunteers, aged 21 to 50 years old, men or women
- •Subjects negative for human immunodeficiency virus (HIV), Hepatitis B virus surface Antigen (HBsAg) and Hepatitis C virus (HCV)
- •Subjects who have not been vaccinated against or had prior exposure to Yellow Fever Virus (YFV)
- •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
- •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
- •Subjects who give written informed consent approved by the Ethical Review Board governing the site
- •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
- •Accessible vein in the forearm for blood collection
- •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
- •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
- •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)
排除标准
- •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
- •History of severe drug and / or food allergies and / or known allergies to the trial product or its components
- •Female subject who is pregnant or breast-feeding
- •History or presence of cardiovascular, respiratory, hepatic, renal, gastrointestinal, neuropsychiatric, or immunosuppressive disorders
- •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
- •Evidence of substance abuse, or previous substance abuse
- •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
- •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
- •Administration of any licensed vaccine within 30 days before the first study vaccine dose.
- •History of any reaction to monoclonal antibodies
- •Any condition that, in the opinion of the Investigator, would complicate or compromise the study or well-being of the subject
- •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:
- •Planned travels to Central America, South America, Africa or any other YFV-endemic countries in the next six (6) months
- •History of thymus gland disease.
- •Diagnosed with cancer or on treatment for cancer with the three (3) years prior to the screening.
研究组 & 干预措施
Safety Arm - 10 mg/kg
Subject will be administered with 10 mg/kg of TY014 via IV infusion over a period of 30 minutes.
干预措施: TY014 (Biological)
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.
干预措施: 0.9% Saline (Other)
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.
干预措施: 0.9% Saline (Other)
Safety Arm - Placebo
Subject will be administered with 0.9% saline via IV infusion over a period of 30 minutes.
干预措施: 0.9% Saline (Other)
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.
干预措施: 0.9% Saline (Other)
Safety Arm - 20 mg/kg
Subject will be administered with 20 mg/kg of TY014 via IV infusion over a period of 30 minutes.
干预措施: TY014 (Biological)
Safety Arm - 5 mg/kg
Subject will be administered with 5 mg/kg of TY014 via IV infusion over a period of 30 minutes.
干预措施: TY014 (Biological)
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.
干预措施: 0.9% Saline (Other)
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.
干预措施: TY014 (Biological)
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.
干预措施: TY014 (Biological)
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.
干预措施: TY014 (Biological)
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.
干预措施: TY014 (Biological)
Safety Arm - 2 mg/kg
Subject will be administered with 2 mg/kg of TY014 via IV infusion over a period of 30 minutes.
干预措施: TY014 (Biological)
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.
干预措施: TY014 (Biological)
结局指标
主要结局
Incidence of Treatment-Emergent Adverse Event (Safety and Tolerability)
时间窗: 84 Days
Presence or absence of infusion reaction (hypersensitivity / anaphylaxis / etc.) in dose cohorts.
Percentage Aviremia Post Treatment (Efficacy Arm only)
时间窗: 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
次要结局
- Maximum Concentration (Cmax) - Pharmacokinetic Assessment(84 Days)
- Time to Maximum Concentration (Tmax) - Pharmacokinetic Assessment(84 Days)
- Area Under the Curve Extrapolated to Infinity (AUC0-∞) - Pharmacokinetic Assessment(84 Days)
- AUC calculated from time of administration to the last measurable concentration (AUC0-last) - Pharmacokinetic Assessment(84 Days)
- Half-Life (t1/2) - Pharmacokinetic Assessment(84 Days)
- Volume of Distribution (Vd) - Pharmacokinetic Assessment(84 Days)
- Viral Load Reduction (Efficacy Arm only)(84 Days)
- Clearance [CL] - Pharmacokinetic Assessment(84 Days)