A Trial to Evaluate the Safety, Pharmacokinetics and Pharmacodynamic Profile of TNM005 in Healthy Adult Subjectsy

Study Overview
=================
Brief Summary
-----------------
The purpose of this clinical trial is to evaluate the safety and tolerability of TNM005 following a single dose by intramuscular (IM) administration in healthy adult subjects The main questions it aims to answer are:1. safety profile；2. PK properties 3. PD properties

Detailed Description
-----------------
This is a randomized, double-blind, placebo-controlled, single ascending dose, phase 1 study designed to evaluate the safety, tolerability, PK, PD (anti-VZV antibody level), and immunogenicity of TNM005, as well as to characterize the PD of VARIZIG, in healthy adult volunteers. The study also includes a cohort in which eight subjects will receive a single dose of VARIZIG 625 IU. This cohort will be conducted in an open-label fashion and may be initiated as early as the first TNM005 cohort is dosed. The study include periods of Screening (up to 28 days), in-patient (treatment on Day 1), and safety follow-up until Day 120.

Official Title
-----------------
A Randomized, Double-blind, Placebo-Controlled, Single Ascending Dose, Phase 1 Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of TNM005 and to Characterize the Pharmacodynamics of TNM005 and VARIZIG in Healthy Adult Volunteers

Conditions
-----------------
Varicella

Intervention / Treatment
-----------------
* Drug: TNM005
* Drug: Placebo
* Drug: VariZIG


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 1) Signed and dated written informed consent; 2) Are willing and able to comply with scheduled visits, blood sampling, laboratory tests, and other study procedures; 3) Healthy males or females, 18-55 years of age (both inclusive); 4) Body mass index (BMI) within 18.5-31.0 kg/m2 (both inclusive) and body weight ≥50.0 kg for males and ≥45.0 kg for females; 5) Have no clinically significant abnormality on physical examination, vital signs, 12-lead ECG, and clinical laboratory tests as determined by the Investigator; 6) Females must be either surgically sterile or under post-menopausal status at Screening or agree to use a highly effective method of contraception from screening until 120 days after IMP dosing. In addition, males who are sexually active and partners of women of childbearing potential must agree to use effective contraception from screening until 120 days after drug administration. Exclusion Criteria: 1) History or evidence of any other acute or chronic disease that, in the opinion of the Investigator, may interfere with the evaluation of the safety or immunogenicity of the drug or compromise the safety of the subject; 2) History of surgery (except minor outpatient surgery) within three months prior to screening or planned surgery during the study; 3) History of receiving monoclonal antibody, immunoglobulin, or blood products within six months prior to dosing; 4) Receipt of systemic immunosuppressive medications; 5) Exposure to any live attenuated vaccine within four weeks prior to drug administration; 6) History of receiving vaccine(s) against zoster; 7) Use of any other drug, including over-the-counter medications, and herbs, within 14 days prior to the drug administration or five half-lives of the drug, whichever is longer, except for contraceptive medication in women of childbearing potential (WOCBP), or concomitant medications that are considered necessary for the subject's welfare and unlikely to interfere with the study; 8) Donated blood >400 mL or significant blood loss equivalent to 400 mL within one month before Screening; or plasma donation within 14 days before Screening; or any plan of blood or blood product donation during the study; 9) Positive test at a screening of any of the following: hepatitis B surface antigen (HBsAg), hepatitis C (HCV) antibody, or human immunodeficiency virus (HIV) antigen/antibody; 10) Known or suspected history of drug abuse within the past five years or with a positive urine drug test at Screening or on Day -1; 11) History of significant alcohol abuse within six months prior to screening or any indication of regular use of more than 14 units of alcohol per week or taking a product containing alcohol two days prior to dosing, or having a positive alcohol breath test on Day -1; 12) Use of ≥five cigarettes or equivalent nicotine-containing product per day on average over three months prior to Screening; or unwilling to refrain from nicotine products during study participation; 13) History of allergic or anaphylactic reaction to a therapeutic or diagnostic monoclonal antibody or IgG-fusion protein; 14) History of allergic or anaphylactic reaction to blood products (only for VARIZIG cohort); 15) IgA deficient subjects at risk for hypersensitivity reaction (only for VARIZIG cohort); 16) Subjects at high risk for thrombotic events, including those with a history of venous or arterial thrombosis, atherosclerosis, or multiple cardiovascular risk factors (only for VARIZIG cohort); 17) Participation in any other clinical studies with chemical or biological drugs or devices within four weeks or five times the half-life of the specific drug/biologics (whichever is longer) before drug administration; 18) Nursing mothers or pregnant women; 19) Subjects considered unsuitable for participating in the study in the opinion of the Investigator.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TNM005 dose level 1/placebo<br>TNM005 on dose level 1 /placebo | Drug: TNM005<br>* single,intramuscular injection<br>Drug: Placebo<br>* single,intramuscular injection<br>|
| Experimental: TNM005 dose level 2/placebo<br>TNM005 on different dose level 2 /placebo | Drug: TNM005<br>* single,intramuscular injection<br>Drug: Placebo<br>* single,intramuscular injection<br>|
| Experimental: TNM005 level 3/placebo<br>TNM005 on dose level 3 /placebo | Drug: TNM005<br>* single,intramuscular injection<br>Drug: Placebo<br>* single,intramuscular injection<br>|
| Experimental: TNM005 dose level 4/placebo<br>TNM005 on dose level 4 /placebo | Drug: TNM005<br>* single,intramuscular injection<br>Drug: Placebo<br>* single,intramuscular injection<br>|
| Experimental: TNM005 dose level 5/placebo<br>TNM005 on dose level 5 /placebo | Drug: TNM005<br>* single,intramuscular injection<br>Drug: Placebo<br>* single,intramuscular injection<br>|
| Active Comparator: VARIZIG<br>VARIZIG 625 IU | Drug: VariZIG<br>* a single dose of VARIZIG 625 IU,intramuscular injection<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of AEs |  | Up to 120 days post dosing | 
| Number of participants Physical examinations abnormalities | Physical examination includes assessments of general appearance, skin, lymph nodes, head.neck, lung, heart, abdomen, spine, extremities, nervous system, etc. | Up to 120 days post dosing | 
| Number of participants with abnormalities of vital signs | Vital signs measured include blood pressure, pulse rate, temperature, and respiration rate. | Up to 120 days post dosing | 
| Number of participants with abnormalities of 12-lead electrocardiogram (ECG) parameters | ECG parameters include heart rate, PR interval, RR interval, ORS duration, QTcF interval. | Up to 120 days post dosing | 
| Number of participants with abnormalities of clinical laboratory tests | Clinical laboratory tests include hematology, biochemistry, coagulation, and urinalysis. | Up to 120 days post dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AUC0-t | Area under the plasma concentration-time curve from time 0 (predose) to the last time point with a detectable plasma concentration (Tlast.). | Up to 120 days post dosing | 
| AUC0-∞ | Area under the plasma concentration-time curve from time 0 (predose) extrapolated to infinite time. | Up to 120 days post dosing | 
| Cmax | Maximum plasma concentration | Up to 120days post dosing | 
| Tmax | Time to reach maximum plasma concentration | Up to 120 days post dosing | 
| t1/2 | Elimination half-life | Up to 120days post dosing | 
| λz | Terminal disposition rate constant | Up to 120days post dosing | 
| CL/F | Apparent clearance | Up to 120days post dosing | 
| Vd/F | Apparent volume of distribution | Up to 120days post dosing | 
| t1/2 of anti-varicella-zoster virus (VZV) antibody level (both baseline corrected and uncorrected) | Elimination half-life of antibody level of anti-VZV | Up to 120days post dosing | 
| ADA | Incidence of anti-drug antibody (ADA) to TNM005 in serum | Up to 120days post dosing |