Safety, Pharmacokinetics, and Pharmacodynamic Testing of Rabies mAb CBB 1

Study Overview
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Brief Summary
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rabies mab CBB 1 is mainly used for passive immunization of patients bitten or scratched by rabies or other animals carrying rabies virus, this study mainly studies the safety, tolerability, pharmacokinetics, neutralizing antibody activity and immunogenic characteristics of rabies mAb CBB 1 in healthy adults

Detailed Description
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Evaluate and compare the safety, tolerability, pharmacokinetics, neutralizing antibody activity and immunogenicity of rabies virus after single doses of rabies mAb CBB 1 or rabies human immunoglobulin (HRIG) in healthy adults. Evaluate and compare the safety, tolerability, pharmacokinetics, neutralizing antibody activity and immunogenicity characteristics of rabies virus after different doses of rabies mAb CBB 1 combination vaccine or HRIG combination vaccine in healthy adults. Comparison of different doses of rabies mAb CBB 1 alone, different doses of rabies mAb CBB 1, combination vaccine or HRIG combination vaccine used in healthy adults after safety, tolerability, pharmacokinetics, rabies virus neutralization antibody activity and immunogenicity characteristics, further evaluation of drug interaction, for subsequent clinical trials to explore the optimal dose.

Official Title
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Multicenter, Randomized, Double-blind, Placebo / Positive Control Evaluation of the First Safety, Pharmacokinetic and Pharmacodynamic Phase I Clinical Trial of Rabies Monomab CBB 1 in Healthy People

Conditions
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Rabies Virus Infection

Intervention / Treatment
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* Drug: Natural full human monoclonal antibody CBB 1 injection
* Drug: Rabies Human Immunoglobulin (HRIG)
* Drug: Natural full human monoclonal antibody CBB 1 injection placebo
* Biological: Lyophilized rabies vaccine for human use (Vero cells)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Before the trial, I have had a detailed understanding of the nature, significance and possible benefits of the trial, the possible inconvenience and potential risks and discomfort, and volunteered to participate in this clinical trial, was able to communicate well with researchers, comply with the requirements of the whole study, and signed a written informed consent; Men or women aged 18 50 (including boundary values) at the time of screening; The weight of female volunteers was 45.0 kg and 80.0 kg, that of male volunteers was 50.0 kg and 80.0 kg, and the body mass index (BMI) was between 18.0 and 27.0 kg/m2 (including boundary value) (BMI= weight kg / height m2); Female volunteers have no fertility or egg donation plan within 14 days before the first dose to 3 months after the end of the trial and voluntarily take effective physical contraception, while male volunteers have no fertility or sperm donation plan within 3 months after the first dose to the trial and voluntarily take effective physical contraception. Exclusion Criteria: Those who are known to be allergic to the study drug (including excipients, similar drugs), or suffer from severe allergic diseases or allergic constitution (such as allergic to two or more drugs, food or pollen), may damage the safety of the volunteers in the judgment of the investigator (inquiry); Those with a clear history of allergy to the essential substances (such as skin disinfectants) that may be exposed to during the test (inquiry); Patients with a history of clinically serious disease within 6 months (180 days) before the first dose and not cured, or patients with acute or chronic diseases that may significantly affect the in vivo process or safety evaluation of the study drug (inquiry); Patients with a previous history of autoimmune diseases or chronic hepatitis (inquiry); Patients with a previous history of convulsions, epilepsy, mental or nervous system, or a family history of convulsions or epilepsy (inquiry); Those who have received major surgery within 3 months (90 days) prior to the first dose, or those who may significantly affect the internal process or safety evaluation of the study drug (inquiry, inquiry); Patients with a history of rabies virus infection or have received rabies vaccination (inquiry); Suspected or clear identification of a history of injuries to warm-blooded mammals in the last 12 months (360 days) (warm-blooded animals refer to animals that can regulate their body temperature, also known as endotherms. Birds and the vast majority of mammals, including the cats and dogs around them, are warm-blooded animals) (inquiry); Having received a vaccine other than the rabies vaccine within 1 month (30 days) prior to the first dose (inquiry); Those who have used a rabies passive immunization preparation or used systemic immunosuppressive agents such as glucocorticoids within 3 months (90 days) prior to the first dose (inquiry, inquiry)； Those who have been used or are in the current period) or who may have a significant impact on the in vivo process or safety evaluation of the study drug (inquiry, inquiry); Any clinical trial drug or device used within 3 months (90 days) prior to the first dose, or <5 half-lives of the last previous trial drug dose (whichever is older), or planned to participate in other clinical trials during the study (inquiry, inquiry); Regular alcohol for 3 months (90 days) before the first dose (3 times a week, and an average of 50° of liquor 200 ml) (inquiry); Those with positive alcohol breath test or test value> 0 mg / 100 ml (examination); Cigarette addiction (more than 10 cigarettes or the same amount of tobacco per day) within 1 month (30 days) before the first dose (inquiry); Those who lost blood / donated more than 400 ml (other than female physiological blood loss) within 3 months (90 days) before the first dose, or who received blood transfusion or used blood products, or planned to donate blood during the trial or within 1 month (30 days) after the end of the trial (inquiry); Those who ingested alcohol-containing products within 24 hours before the first dose (inquiry); Abnormalities at the administration site (such as inflammation, induration, redness, large area scar or tattoo, etc.) shall affect the administration or the clinical observer (examination); Those with a history of substance abuse (inquiry); Those who are screened positive for substance abuse during the screening period (examination); Those who are positive for the initial HIV screening during the screening period (screening); two half and half qualitative tests of hepatitis B during the screening period (examination); Patients with positive results for hepatitis C virus antibody or treponema pallidum antibody during the screening period (examination); Physical examination, vital signs (respiration, blood pressure, pulse rate), electrocardiogram, other laboratory tests (laboratory tests not listed separately) or other auxiliary examination results are judged as abnormal and clinically significant by the study doctor (examination); Ear temperature during the screening period is> 37.5℃ (examination); Women currently in pregnancy or lactation (inquiry); Positive screening pregnancy test (examination); Patients with a history of needle acupuncture, blood sickness, or unable to tolerate venipuncture (inquiry); The volunteers may be unable to cooperate with the study for other reasons or the investigators is not unsuitable for inclusion.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: There were 152 healthy people aged 10-50 years, divided into two test groups: 76 rabies mAb CBB 1 alone and 76 rabies mAb CBB 1 combined with rabies vaccine administration, which were divided into 4 groups according to different doses
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental group<br>Natural full human monoclonal antibody CBB 1 injection：Each dose (2.5ml) contained 0.5 mg / natural monoclonal antibody ml CBB 1 Ingredients: 25 mM citrate buffer, 125 mM sodium chloride, 0.02% (w / v) polysorbate 20 and water for injection Character: colorless to pale green and yellow liquid Specification: 1.25 mg (2.5 ml) / bottle Mode of administration: intramuscular injection of the vastus lateralis muscle. Usage and dosage: The injection dose was calculated according to the group and body weight of the volunteer. On day 0, unilateral or bilateral extrafemoral muscle group injections were selected by dose, with no more than 5 mL at each site, and at least 2.5 cm apart. | Drug: Natural full human monoclonal antibody CBB 1 injection<br>* Active ingredient: natural full human monoclonal antibody CBB 1 containing 0.5 mg / ml per dose (2.5ml) Ingredients: 25 mM citrate buffer, 125 mM sodium chloride, 0.02% (w / v) polysorbate 20 and water for injection<br>Biological: Lyophilized rabies vaccine for human use (Vero cells)<br>* Active ingredient: inactivated rabies virus fixed poison<br>|
| Active Comparator: Positive control group<br>Rabies Human Immunoglobulin (HRIG) Active ingredient: Rabid human immunoglobulin Specification: 200 IU / 2 ml / bottle Administration mode: intramuscular injection of the vastus lateral muscle group. Usage and dosage: the injection dose was calculated according to the body weight of the volunteer. On day 0, unilateral or bilateral extrafemoral muscle group injections were selected by dose, with no more than 5 mL at each site and at least 2.5 cm apart | Drug: Rabies Human Immunoglobulin (HRIG)<br>* Active ingredient: Rabid human immunoglobulin<br>Biological: Lyophilized rabies vaccine for human use (Vero cells)<br>* Active ingredient: inactivated rabies virus fixed poison<br>|
| Placebo Comparator: Placebo group<br>Healthy people in placebo group will receive a dose of placebo | Drug: Natural full human monoclonal antibody CBB 1 injection placebo<br>* Composition: 25 mM citrate buffer, 125 mM sodium chloride, 0.02% (w / v) polysorbate 20 and water for injection<br>Biological: Lyophilized rabies vaccine for human use (Vero cells)<br>* Active ingredient: inactivated rabies virus fixed poison<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety evaluation index | All observed adverse events, serious adverse events, including but not limited to: Clinical indicators Physical examination; vital signs; 12-lead ECG; local reaction; systemic reaction. Laboratory indicators Laboratory tests: blood routine, urine routine, blood biochemistry (including liver function, fasting blood glucose, renal function, blood lipid, myocardial enzyme spectrum and electrolyte), blood coagulation routine, viral serology (hepatitis B two half, hepatitis C virus antibodies, human immunodeficiency virus antibodies and treponema antibodies), blood / urine pregnancy test (fertility only women); other auxiliary tests: chest radiograph (positive) and abdominal B ultrasound (including liver, gallbladder, pancreas, spleen and kidney). | Twelve months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PK evaluation index | (1) PK evaluation index Peak Plasma Concentration (Cmax) | Twelve months | 
| PK evaluation index | (1) PK evaluation index Area under the plasma concentration versus time curve (AUC) | Twelve months | 
| PK evaluation index | (1) PK evaluation index Maximum peak time (Tmax) | Twelve months | 
| PK evaluation index | (1) PK evaluation index Half-life period(T1/2) | Twelve months | 
| PK evaluation index | (1) PK evaluation index MeanResidenceTime（MRT） | Twelve months | 
| PK evaluation index | (1) PK evaluation index Apparent clearance rate (CL / F) | Twelve months | 
| PD evaluation index | (2) PD evaluation index Positive rate of RVNA antibody on days 1,3,5,7,14,28 and 42 after medication (percentage of GMT 0.5 IU / ml volunteers); Neutralising antibody (RVNA) activity at days 0.5,1,2,3,5,7,10,14,1,21,28,42,56,84 and 105 after administration. | Twelve months | 
| Immunogenicity evaluation index | (3) Immunogenicity evaluation index ADA positivity on days 14,28,56 and 105 after administration. If ADA positive, they will continue to be evaluated as rabies mAb CBB 1 neutralizing antibody. | Twelve months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Safety, Immunogenicity, Rabies Virus Neutralizing Antibodies