Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of TNM002 in Healthy Adults

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics properties of TNM002 following a single intramuscular dose in healthy adult subjects.

Detailed Description
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The study a randomized, double-blinded, placebo-controlled, dose-escalation phase I trial. A total of 32 healthy adult subjects will be enrolled into 4 cohorts sequentially. Each participant will receive a single IM dose of TNM002 or placebo according to the cohort in which they were enrolled. After injection (Day 1), participants remain in the study site for observation up to 5 days. Following completion of the safety assessments and sampling for PK/PD analyses on Day 4, participants will be discharged from the study site. On Day 8, 15, 29, 43, 64 and 85, participants will return for safety assessments.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Phase I Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Following Intramuscular Administration of a Single Dose of TNM002 in Healthy Subjects

Conditions
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Healthy Adult Subjects

Intervention / Treatment
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* Biological: TNM002 Dosage 1 (10 μg/kg)
* Biological: Placebo
* Biological: TNM002 Dosage 2 (35 μg/kg)
* Biological: Placebo
* Biological: TNM002 Dosage 3 (100 μg/kg)
* Biological: Placebo
* Biological: TNM002 Dosage 4 (250 μg/kg)
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Each subject must meet the following criteria to be enrolled in this study: Healthy male or female, 18-55 years of age (both inclusive); Able to give signed written informed consent form; Able to well communicate with investigators as well as understand and adhere to the requirements of this study. Body mass index (BMI, weight [kg]/height [m]2) within 18.0-32.0 kg/m2 (both inclusive); Blood Pressure (BP) and 12-lead ECG showing no clinically significant abnormalities at the discretion of the Principal Investigator during screening; Subjects having no clinically significant abnormality on physical examination, clinical laboratory tests, liver function or kidney function as determined by Principal Investigator (PI); Females must be either under surgical sterile (i.e. had a bilateral tubal ligation, hysterectomy, or bilateral oophorectomy at least 6 months before the first dose of study drug) or under postmenopausal for at least 1 year before the first dose of study drug or agree to use an acceptable method of contraception from screening until 90 days after last study drug administration. Males who are sexually active and who are partners of women of childbearing potential must agree to use effective contraception from screening until 90 days after last drug administration. acceptable method of contraception Use of intrauterine device Use of oral, injected or implanted hormonal methods of contraception Concomitant use of barrier contraception method Surgical contraception methods (e.g., vasectomy, salpingectomy, hysterectomy, etc.) Exclusion Criteria: Subjects who meet any of the following criteria will be excluded from the study: History or evidence of severe drug or excipient allergy, or hypersensitivity to other therapeutic mAbs; History or evidence of autoimmune disease or possible immunodeficiency state, including positive screening test for HIV; History or evidence of chronic hepatitis, including positive screening test for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody; History or evidence of tetanus infection, or exposure to tetanus vaccine within 6 months prior to the fist drug administration; Exposure to any live attenuated vaccine within 4 weeks prior to the fist drug administration; Exposure to any inactivated vaccine within 2 weeks prior to the fist drug administration; History or evidence of any other acute or chronic disease that, in the opinion of the investigator, may have interfered with the evaluation of the safety or immunogenicity of the drug or compromised the safety of the subject; for example, a clinically relevant history of respiratory, thyroid, gastrointestinal, renal, hepatic, hematological, lymphatic, oncologic, cardiovascular, psychiatric, neurological, musculoskeletal, genitourinary, infective, inflammatory, immunological, dermatological, or connective tissue disease Subjects with surgery (except for minor outpatient surgery) within past 3 months prior to screening, or planned surgery during study; Subjects with intolerance or insufficient venous access to permit regular venepuncture; Known or suspected history of drug abuse within the past 5 years or with positive urine drug test at the screening; Donated blood >400 mL or significant blood loss equivalent to 400 mL or received blood transfusion within 3months of screening; or donated blood >200 mL or significant blood loss equivalent to 200 mL within 1 month prior to the screening; Participation in any other clinical studies with chemical or biological drugs or device within 4 weeks or 5 times the half-life of the specific drug/biologics (whichever is longer), prior to the first drug administration; Use of any other drug, including over-the-counter medications, herb medicines within 14 days prior to the first drug administration (except for contraceptive medication in WOCBP, or concomitant medications that are considered necessary for the subject's welfare and unlikely to interfere with the study); Receipt of an Ig or blood product within 90 days prior to the first drug administration; Receipt of immunosuppressive medications, other than inhaled or topical immunosuppressant drugs, within 45 days prior to the first drug administration; Habitual use of nicotine products or smoking within 3 months (more than 5 cigarettes per day) prior to screening or unwilling to refrain from nicotine products during study participation; History of significant alcohol abuse within 6 months of screening or any indication of regular use of more than 14 units of alcohol per week (1 Unit=360 mL of beer or 45 mL of alcohol 40% or 150 mL of wine) or taking a product containing alcohol 2 days prior to dosing, or having a positive alcohol breath test during the screen period.; Malignancy within 5 years of screening visit (except basal cell skin carcinoma); Subject who is considered unsuitable for participating in the study in the opinion of investigator; Nursing mothers or pregnant women.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1 TNM002 10 μg/kg/Placebo<br>Sentinel dosing will be conducted for Cohort 1. Two participants will be dosed (1 with TNM002, 1 with placebo) at least 72 hours prior to subsequent dosing. The remaining participants will only be dosed if no significant safety signals are identified in the sentinel participants. In total, eight subjects will be randomly assigned to receive either TNM002 or placebo at a 3:1 ratio (i.e. 6 subjects receive TNM002 and 2 with placebo). | Biological: TNM002 Dosage 1 (10 μg/kg)<br>* TNM002 (human monoclonal antibody against tetanus toxin), 10 μg/kg, Intramuscular injection, given once.<br>Biological: Placebo<br>* placebo to match TNM002 Dosage 1, given once<br>|
| Experimental: Cohort 2 TNM002 35 μg/kg/Placebo<br>Eight subjects will be randomly assigned to receive either TNM002 or placebo at a 3:1 ratio (i.e. 6 subjects receive TNM002 and 2 with placebo). | Biological: TNM002 Dosage 2 (35 μg/kg)<br>* TNM002 (human monoclonal antibody against tetanus toxin), 35 μg/kg, Intramuscular injection, given once<br>Biological: Placebo<br>* placebo to match TNM002 Dosage 2, given once<br>|
| Experimental: Cohort 3 TNM002 100 μg/kg/Placebo<br>Eight subjects will be randomly assigned to receive either TNM002 or placebo at a 3:1 ratio (i.e. 6 subjects receive TNM002 and 2 with placebo). | Biological: TNM002 Dosage 3 (100 μg/kg)<br>* TNM002 (human monoclonal antibody against tetanus toxin), 100 μg/kg, Intramuscular injection, given once<br>Biological: Placebo<br>* placebo to match TNM002 Dosage 3, given once<br>|
| Experimental: Cohort 4 TNM002 250 μg/kg/Placebo<br>Eight subjects will be randomly assigned to receive either TNM002 or placebo at a 3:1 ratio (i.e. 6 subjects receive TNM002 and 2 with placebo). | Biological: TNM002 Dosage 4 (250 μg/kg)<br>* TNM002 (human monoclonal antibody against tetanus toxin), 250 μg/kg, Intramuscular injection, given once<br>Biological: Placebo<br>* placebo to match TNM002 Dosage 4, given once<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of adverse events | The investigator will assess the intensity for each AE reported during the study based on the investigator's clinical judgment. Adverse events will be recorded according to CTCAE V5.0. | Up to 105 days post dosing | 
| Clinically significant abnormality in physical examinations | clinically significant abnormality in general condition, skin, eyes/ears/nose/mouth/throat, neck/thyroid, chest/lungs, heart, vascular system, lymph nodes, abdomen, extremities, nervous systems/reflexes, musculoskeletal, spine | Up to 105 days post dosing | 
| Change in RR intervals (msec) | Measured using a 12 Lead Electrocardiogram | Up to 105 days post dosing | 
| Change in PR intervals (msec) | Measured using a 12 Lead Electrocardiogram | Up to 105 days post dosing | 
| Change in QRS duration (msec) | Measured using a 12 Lead Electrocardiogram | Up to 105 days post dosing | 
| Change in QT intervals (msec) | Calculated using measurements by a 12 Lead Electrocardiogram | Up to 105 days post dosing | 
| Change in QTcB intervals (msec) | Calculated using measurements by a 12 Lead Electrocardiogram | Up to 105 days post dosing | 
| Change in QTcF intervals (msec) | Calculated using measurements by a 12 Lead Electrocardiogram | Up to 105 days post dosing | 
| Change in Semi recumbent blood pressure (mmHg) |  | Up to 105 days post dosing | 
| Change in pulse rate (bpm) |  | Up to 105 days post dosing | 
| Change in body temperature (celsius) |  | Up to 105 days post dosing | 
| Change in Hematocrit (ratio) | Measured by hematology test | Up to 105 days post dosing | 
| Change in Haemoglobin (g/L) | Measured by hematology test | Up to 105 days post dosing | 
| Change in Mean corpuscular hemoglobin (pg) | Measured by hematology test | Up to 105 days post dosing | 
| Change in Mean corpuscular hemoglobin concentration (g/L) | Measured by hematology test | Up to 105 days post dosing | 
| Change in Mean corpuscular volume (fL) | Measured by hematology test | Up to 105 days post dosing | 
| Change in Platelet count (cells x 10^9/L)) | Measured by hematology test | Up to 105 days post dosing | 
| Change in Red blood cell count (cells x 10^12/L) | Measured by hematology test | Up to 105 days post dosing | 
| Change in White blood cell count (cells x 10^9/L) | Measured by hematology test | Up to 105 days post dosing | 
| Change in differential leukocyte count (cells x 10^9/L) | Including eosinophils, monocytes, lymphocytes, basophils, and neutrophils, Measured by hematology test | Up to 105 days post dosing | 
| Change in Serum Alanine Aminotransferase (ALT) (U/L) | measured by serum chemistry | Up to 105 days post dosing | 
| Change in Serum Albumin (g/L) | measured by serum chemistry | Up to 105 days post dosing | 
| Change in Serum Alkaline Phosphatase (ALP) (U/L) | measured by serum chemistry | Up to 105 days post dosing | 
| Change in Serum Aspartate Aminotransferase (AST) (U/L) | measured by serum chemistry | Up to 105 days post dosing | 
| Change in Serum Total Bilirubin (umol/L) | measured by serum chemistry | Up to 105 days post dosing | 
| Change in Serum Blood urea nitrogen (BUN) (mmol/L) | measured by serum chemistry | Up to 105 days post dosing | 
| Change in Serum Calcium (mmol/L) | measured by serum chemistry | Up to 105 days post dosing | 
| Change in Serum Chloride (mmol/L) | measured by serum chemistry | Up to 105 days post dosing | 
| Change in Serum Cholesterol (mmol/L) | measured by serum chemistry | Up to 105 days post dosing | 
| Change in Serum Creatinine (umol/L) | measured by serum chemistry | Up to 105 days post dosing | 
| Change in Serum Creatine Kinase (U/L) | measured by serum chemistry | Up to 105 days post dosing | 
| Change in Serum Glucose (mmol/L) | measured by serum chemistry | Up to 105 days post dosing | 
| Change in Serum Lactate Dehydrogenase (U/L) | measured by serum chemistry | Up to 105 days post dosing | 
| Change in Serum Phosphorus (mmol/L) | measured by serum chemistry | Up to 105 days post dosing | 
| Change in Serum Potassium (mmol/L) | measured by serum chemistry | Up to 105 days post dosing | 
| Change in Serum Total protein (g/L) | measured by serum chemistry | Up to 105 days post dosing | 
| Change in Urine Bilirubin (U-BIL) | measured by Urinalysis | Up to 105 days post dosing | 
| Change in Urine Glucose (GLU) (mg/dL) | measured by Urinalysis | Up to 105 days post dosing | 
| Change in Urine erythrocytes (U-RBC) | measured by Urinalysis | Up to 105 days post dosing | 
| Change in Urinary leukocyte (U-LEU) | measured by Urinalysis | Up to 105 days post dosing | 
| Change in Urine nitrites (U-NIT) | measured by Urinalysis | Up to 105 days post dosing | 
| Change in Urine protein (U-PRO) | measured by Urinalysis | Up to 105 days post dosing | 
| Change in Urine specific gravity (U-SG) | measured by Urinalysis | Up to 105 days post dosing | 
| Change in Urine urobilinogen (URO) | measured by Urinalysis | Up to 105 days post dosing | 
| Change in Prothrombin time (sec) | measured by Blood Coagulation test | Up to 105 days post dosing | 
| Change in Activated partial thromboplastin time (APTT)(sec) | measured by Blood Coagulation test | Up to 105 days post dosing | 
| Change in fibrinogen (g/L) | measured by Blood Coagulation test | Up to 105 days post dosing | 
| Change in international normalized ratio (INR) | measured by Blood Coagulation test | Up to 105 days post dosing | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-TNM002 antibodies | The numbers of subjects who developed anti-TNM002 antibodies | Up to 105 days post dosing | 
| Anti-TNM002 antibodies | The percentages of subjects who developed anti-TNM002 antibodies | Up to 105 days post dosing | 
| Maximum observed plasma concentration (Cmax) | Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above | Up to 105 days post dosing | 
| Time of maximum plasma concentration (Tmax) | Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above | Up to 105 days post dosing | 
| Terminal half-life (T1/2) | Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above | Up to 105 days post dosing | 
| Area under the plasma concentration-time curve from time-zero to the time of the last measurable concentration (AUC0-last) | Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above | Up to 105 days post dosing | 
| Area under the plasma concentration-time curve from time-zero extrapolated to infinite time (AUC0-inf) | Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above | Up to 105 days post dosing | 
| Apparent oral clearance (CL/F) | Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above | Up to 105 days post dosing | 
| Apparent volume of distribution (Vz/F) | Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above | Up to 105 days post dosing | 
| Mean retention time (MRT) | Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above | Up to 105 days post dosing | 
| Lambda z - the reciprocal of elimination rate constant | Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above | Up to 105 days post dosing | 
| The ratio of area under the plasma concentration-time curve from time-zero to the time of the last measurable concentration (AUC0-last) extrapolated to AUC0-inf over AUC0-inf (% AUCex) | Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above | Up to 105 days post dosing |