Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of TNM002 in Healthy Adults
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Cohort 1 TNM002 10 μg/kg/Placebo 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)
TNM002 (human monoclonal antibody against tetanus toxin), 10 μg/kg, Intramuscular injection, given once.
Biological: Placebo
placebo to match TNM002 Dosage 1, given once
|
| Experimental: Cohort 2 TNM002 35 μg/kg/Placebo 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)
TNM002 (human monoclonal antibody against tetanus toxin), 35 μg/kg, Intramuscular injection, given once
Biological: Placebo
placebo to match TNM002 Dosage 2, given once
|
| Experimental: Cohort 3 TNM002 100 μg/kg/Placebo 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)
TNM002 (human monoclonal antibody against tetanus toxin), 100 μg/kg, Intramuscular injection, given once
Biological: Placebo
placebo to match TNM002 Dosage 3, given once
|
| Experimental: Cohort 4 TNM002 250 μg/kg/Placebo 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)
TNM002 (human monoclonal antibody against tetanus toxin), 250 μg/kg, Intramuscular injection, given once
Biological: Placebo
placebo to match TNM002 Dosage 4, given once
|
Outcome Measures
Primary Outcome Measures
- Incidence and severity of adverse events [Up to 85 days post dosing]
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.
- Clinically significant abnormality in physical examinations [Up to 85 days post dosing]
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
- Change in RR intervals (msec) [Up to 85 days post dosing]
Measured using a 12 Lead Electrocardiogram
- Change in PR intervals (msec) [Up to 85 days post dosing]
Measured using a 12 Lead Electrocardiogram
- Change in QRS duration (msec) [Up to 85 days post dosing]
Measured using a 12 Lead Electrocardiogram
- Change in QT intervals (msec) [Up to 85 days post dosing]
Calculated using measurements by a 12 Lead Electrocardiogram
- Change in QTcB intervals (msec) [Up to 85 days post dosing]
Calculated using measurements by a 12 Lead Electrocardiogram
- Change in QTcF intervals (msec) [Up to 85 days post dosing]
Calculated using measurements by a 12 Lead Electrocardiogram
- Change in Semi recumbent blood pressure (mmHg) [Up to 85 days post dosing]
- Change in pulse rate (bpm) [Up to 85 days post dosing]
- Change in body temperature (celsius) [Up to 85 days post dosing]
- Change in Hematocrit (ratio) [Up to 85 days post dosing]
Measured by hematology test
- Change in Haemoglobin (g/L) [Up to 85 days post dosing]
Measured by hematology test
- Change in Mean corpuscular hemoglobin (pg) [Up to 85 days post dosing]
Measured by hematology test
- Change in Mean corpuscular hemoglobin concentration (g/L) [Up to 85 days post dosing]
Measured by hematology test
- Change in Mean corpuscular volume (fL) [Up to 85 days post dosing]
Measured by hematology test
- Change in Platelet count (cells x 10^9/L)) [Up to 85 days post dosing]
Measured by hematology test
- Change in Red blood cell count (cells x 10^12/L) [Up to 85 days post dosing]
Measured by hematology test
- Change in White blood cell count (cells x 10^9/L) [Up to 85 days post dosing]
Measured by hematology test
- Change in differential leukocyte count (cells x 10^9/L) [Up to 85 days post dosing]
Including eosinophils, monocytes, lymphocytes, basophils, and neutrophils, Measured by hematology test
- Change in Serum Alanine Aminotransferase (ALT) (U/L) [Up to 85 days post dosing]
measured by serum chemistry
- Change in Serum Albumin (g/L) [Up to 85 days post dosing]
measured by serum chemistry
- Change in Serum Alkaline Phosphatase (ALP) (U/L) [Up to 85 days post dosing]
measured by serum chemistry
- Change in Serum Aspartate Aminotransferase (AST) (U/L) [Up to 85 days post dosing]
measured by serum chemistry
- Change in Serum Total Bilirubin (umol/L) [Up to 85 days post dosing]
measured by serum chemistry
- Change in Serum Blood urea nitrogen (BUN) (mmol/L) [Up to 85 days post dosing]
measured by serum chemistry
- Change in Serum Calcium (mmol/L) [Up to 85 days post dosing]
measured by serum chemistry
- Change in Serum Chloride (mmol/L) [Up to 85 days post dosing]
measured by serum chemistry
- Change in Serum Cholesterol (mmol/L) [Up to 85 days post dosing]
measured by serum chemistry
- Change in Serum Creatinine (umol/L) [Up to 85 days post dosing]
measured by serum chemistry
- Change in Serum Creatine Kinase (U/L) [Up to 85 days post dosing]
measured by serum chemistry
- Change in Serum Glucose (mmol/L) [Up to 85 days post dosing]
measured by serum chemistry
- Change in Serum Lactate Dehydrogenase (U/L) [Up to 85 days post dosing]
measured by serum chemistry
- Change in Serum Phosphorus (mmol/L) [Up to 85 days post dosing]
measured by serum chemistry
- Change in Serum Potassium (mmol/L) [Up to 85 days post dosing]
measured by serum chemistry
- Change in Serum Total protein (g/L) [Up to 85 days post dosing]
measured by serum chemistry
- Change in Urine Bilirubin (U-BIL) [Up to 85 days post dosing]
measured by Urinalysis
- Change in Urine Glucose (GLU) (mg/dL) [Up to 85 days post dosing]
measured by Urinalysis
- Change in Urine erythrocytes (U-RBC) [Up to 85 days post dosing]
measured by Urinalysis
- Change in Urinary leukocyte (U-LEU) [Up to 85 days post dosing]
measured by Urinalysis
- Change in Urine nitrites (U-NIT) [Up to 85 days post dosing]
measured by Urinalysis
- Change in Urine protein (U-PRO) [Up to 85 days post dosing]
measured by Urinalysis
- Change in Urine specific gravity (U-SG) [Up to 85 days post dosing]
measured by Urinalysis
- Change in Urine urobilinogen (URO) [Up to 85 days post dosing]
measured by Urinalysis
- Change in Prothrombin time (sec) [Up to 85 days post dosing]
measured by Blood Coagulation test
- Change in Activated partial thromboplastin time (APTT)(sec) [Up to 85 days post dosing]
measured by Blood Coagulation test
- Change in fibrinogen (g/L) [Up to 85 days post dosing]
measured by Blood Coagulation test
- Change in international normalized ratio (INR) [Up to 85 days post dosing]
measured by Blood Coagulation test
Secondary Outcome Measures
- Anti-TNM002 antibodies [Up to 85 days post dosing]
The numbers of subjects who developed anti-TNM002 antibodies
- Anti-TNM002 antibodies [Up to 85 days post dosing]
The percentages of subjects who developed anti-TNM002 antibodies
- Maximum observed plasma concentration (Cmax) [Up to 85 days post dosing]
Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above
- Time of maximum plasma concentration (Tmax) [Up to 85 days post dosing]
Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above
- Terminal half-life (T1/2) [Up to 85 days post dosing]
Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above
- Area under the plasma concentration-time curve from time-zero to the time of the last measurable concentration (AUC0-last) [Up to 85 days post dosing]
Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above
- Area under the plasma concentration-time curve from time-zero extrapolated to infinite time (AUC0-inf) [Up to 85 days post dosing]
Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above
- Apparent oral clearance (CL/F) [Up to 85 days post dosing]
Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above
- Apparent volume of distribution (Vz/F) [Up to 85 days post dosing]
Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above
- Mean retention time (MRT) [Up to 85 days post dosing]
Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above
- Lambda z - the reciprocal of elimination rate constant [Up to 85 days post dosing]
Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above
- 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) [Up to 85 days post dosing]
Estimated by non-compartmental analysis (NCA) with WinNonlin Version 7. 0 or above
Other Outcome Measures
- Tetanus-antibody titer in serum [Up to 85 days post dosing]
- Time to achieve the maximum tetanus-antibody titer [Up to 85 days post dosing]
- The percentage of subjects with a change of titer ≥ 0.2 IU/mL from the baseline [Up to 85 days post dosing]
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Scientia Clinical Research | Sydney | New South Wales | Australia | 2031 |
Sponsors and Collaborators
- Trinomab Biotech Co., Ltd.
- TIGERMED AUSTRALIA PTY LIMITED
Investigators
- Principal Investigator: Charlotte Lemech, FRACP, Scientia Clinical Research Ltd
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- TNM002-P1-AU01