A Phase III Clinical Study to Evaluate SYN023's Efficacy and Safety

Study Overview
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Brief Summary
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This is a Phase 3, blinded, randomized study of SYN023 compared to a China licensed Human Rabies Immunoglobulin (a Rabies immune globulin from human sources, HRIG) for the prevention of rabies as part of post-exposure prophylaxis (PEP). The trial will enroll the World Health Organization (WHO) Category III rabies exposure subjects. The subject's death and rabies data will be reviewed by Data and safety monitoring board (DSMB) to confirm the safety. Besides, rabies vaccine would be administered after Study Drug in each group. This trial is proposed to further the licensure of SYN023 to provide an effective PEP alternative available to those exposed persons who need such a product. A placebo-controlled rabies trial is unethical thus HRIG is selected as the control group. Rabies immune globulin from equine and human sources (HRIG) have been evaluated in many trials and HRIG is the standard of care in China.

Detailed Description
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This is a Phase 3, randomized, blinded, and active controlled study of SYN023 compared with a China licensed HRIG for PEP of patients who have been confirmed to have met all inclusion/exclusion criteria for their treatment group. 1000 patients aged 18 and above with the World Health Organization (WHO) Category III rabies exposure should be enrolled as planned and randomly assigned to the experimental group and the control group based on a ratio of 3: 1 through on-site stratification as part of PEP. All subjects should receive wound infiltration injection of SYN023 or HRIG on Study Day 1 (wound conditions should be described and recorded before injection, including diameter, depth, expansion treatment, etc.), and should also simultaneously receive intramuscular injection of one dose of the freeze-dried rabies vaccine for human use (Vero cells) into the deltoid muscle. In accordance with the Essen Scheme, each subject also needs to receive one dose of the freeze-dried rabies vaccine for human use (Vero cells) on Study Days 4, 8, 15, and 29 respectively. 3.0 mL of venous blood samples should be collected 8 times from each subject prior to administration and on Study Day 4, 8, 15, 43, 99, 183, and 365 post administration of study drug. Relevant information should be collected from the subjects through follow-up visits, such as occurrence of rabies and survival conditions. RVNA should be assayed through rapid fluorescence focus inhibition test (RFFIT). Local adverse events related to the SYN023 injection sites and injection sites of the first dose and second dose of rabies vaccine, and systemic adverse events (AE) other than injection sites should be collected within 7 days after administration; local adverse events related to the injection sites of the third dose, fourth dose and fifth dose of rabies vaccine, and systemic adverse events (AE) other than the injection sites should be collected 7 days after administration. In addition, all adverse events occurring within 43 days after administration should be collected, and pregnancy conditions in 6 months after administration and all serious adverse events (SAE) occurring during the study period should be collected.

Official Title
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A Phase III Randomized Blinded Study to Evaluate SYN023 Compared to Human Rabies Immune Globulin in Post Exposure Prophylaxis of Rabies in Adults With Category III Rabies Exposure Risks

Conditions
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Rabies, Communicable Disease, Virus Diseases, Rhabdoviridae Infections, Mononegavirales Infections, RNA Virus Infections

Intervention / Treatment
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* Biological: SYN023
* Biological: Human Rabies Immune Globulin (HRIG)
* Biological: Rabies Vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is age ≥18 years, on Study Day 1 with legal identification documents, and plan to live in the local administration area during the study; Category III rabies exposure within 24 hours before Study Drug receipt ; Completed written informed consent process, and signed the informed consent forms; Subjects with the ability to understand the study procedure. And agreed to complete all follow-ups; Female subjects are not in pregnancy (with negative results of urine pregnancy tests before vaccination) and are not in the period of breast feeding, and agree to avoid pregnancy within 121 days after administration; Those who have an armpit temperature ≤ 37.0 °C. Exclusion Criteria: Previous receipt of equine or human (rabies) globulin or rabies vaccination prior to randomization; Clinical evidence of rabies infection; Category I and Category II rabies exposure; Had fever (armpit temperature ≥ 38.5 °C) within 3 days before Study Day 1, or in the acute episode of any chronic diseases; Received immunoglobulin or blood products (except for the anti-tetanus immunoglobulin) within 43 days before Study Day 1, or plan to use any such product (except for the anti-tetanus immunoglobulin) during the study; Received systemic immunosuppressant medication such as systemic corticosteroids but not limited to systemic corticosteroids within 43 days before Study Day 1; History of any immunodeficiency disease (for example: AIDS, systemic lupus erythematosus, etc.); or Laboratory evidence of previous or current immunodeficiency disease, including, but not limited to, any laboratory evidence of HIV infection; History of spleen function deficiency or function injury, such as no spleen caused by any cause (such as splenectomy); History of any severe allergy for vaccination, such as systemic urticaria, allergic laryngeal edema, anaphylactoid purpura, local allergic necrosis (Arthus reaction), angioedema, anaphylactic shock, etc., or allergic to any ingredient of the study drug/vaccine; Previous receipt of any study product (drug, vaccine, biological product or medical device) within 6 months before Study Day 1, or plan to participate in any other clinical study during this study period; History of or clinical evidence of any systemic disease, acute disease or chronic disease (such as convulsions, epilepsy, encephalopathy, nephrotic syndrome, etc.) that the investigator considers to be likely to interfere with safety or efficacy assessment of the study; Previous medical history that may compromise the safety of the subject in the study according to the opinion of the principal investigator.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: In this study, 1000 subjects aged 18 and over who had Grade 3 exposure to rabies virus were intended to be enrolled, and randomly assigned to the experimental group and the control group (3:1). Both groups were immunized according to PEP procedures for rabies.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental Group: SYN023+Rabies Vaccine<br>SYN023: Interventions: are administered by direct injection into the wound or by subcutaneous or intramuscular injection when this is not possible SYN023 is an equal mass mixture of CTB011 and CTB012, two monoclonal antibodies that exhibit a wide spectrum of activity against various wild-type rabies strains in vitro. Dosage form: 6mg/2mL, liquid; Dosage: 0.3 mg/kg of SYN023; Frequency/duration: at Day 1 Rabies vaccine : Interventions: should be administered in deltoid muscle Dosage form: >=2.5 IU, freeze-dried vaccine, reconstitute into 0.5 mL before use Dosage: 0.5 mL after reconstitution Frequency/duration: at Day 1, 4, 8, 15, 29 | Biological: SYN023<br>* The finished product of SYN023 is a mixture of 3.0 mg/mL CTB011 and 3.0 mg/mL CTB012 at a ratio of 1:1. SYN023 is a sterile and preservative-free injection, and the excipient contains 25 mM histidine (3.879 mg/mL), 150 mM sodium chloride (8.766 mg/mL) and 0.02% polysorbate 80 (0.2 mg/mL) and pH of 6.0. Each vial contains 2.15 mL of SYN023, or 6.45 mg of monoclonal antibody. The glass bottle was closed with a 13 mm bromobutyl rubber stopper, a 13 mm aluminum crimping cap and a polypropylene flip-open lid.<br>* Other names: A Humanized Anti-Rabies Molecular antibodies cocktails;Biological: Rabies Vaccine<br>* Interventions: The Chinese licensed rabies vaccine should be administered in deltoid muscle Dosage form: >=2.5 IU, freeze-dried vaccine, reconstitute into 0.5 milliliters (mL) before use Dosage: 0.5 mL after reconstitution Frequency/duration: at Day 1, 4, 8, 15, 29<br>* Other names: Freeze-dried Rabies Vaccine for Human Use (Vero Cells);|
| Active Comparator: Control Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine<br>Human Rabies Immune Globulin (HRIG): Interventions: are administered by direct injection into the wound or by subcutaneous or intramuscular injection when this is not possible Dosage form: 100 IU/mL, liquid; Dosage: 20 IU/kg; Frequency/duration: at Day 1 Rabies vaccine : Interventions: should be administered in deltoid muscle Dosage form: >=2.5 IU, freeze-dried vaccine, reconstitute into 0.5 mL before use; Dosage: 0.5 milliliters (mL) after reconstitution; Frequency/duration: at Day 1, 4, 8, 15, 29 | Biological: Human Rabies Immune Globulin (HRIG)<br>* The HRIG is a Chinese licensed Human Rabies Immunoglobulin, which are derived from human plasma, and then purified and filled in the injectable vial form. The HRIG is indicated for the Post-exposure Prophylactic (PEP) of Rabies<br>Biological: Rabies Vaccine<br>* Interventions: The Chinese licensed rabies vaccine should be administered in deltoid muscle Dosage form: >=2.5 IU, freeze-dried vaccine, reconstitute into 0.5 milliliters (mL) before use Dosage: 0.5 mL after reconstitution Frequency/duration: at Day 1, 4, 8, 15, 29<br>* Other names: Freeze-dried Rabies Vaccine for Human Use (Vero Cells);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 8 | Rabies Virus Neutralizing Activity (RVNA) was assessed using Rapid Fluorescent Focus Inhibition Test (RFFIT). | Day 8 | 
| Number of Probable or Confirmed Rabies Cases | WHO's Classification of Rabies Cases: Suspected case: refers to a case that satisfies the definition of clinical case; Probable case: refers to a suspected case with a reliable medical history of contact with any suspected animal infected with the rabies virus; Confirmed case: refers to a suspected or probable case that is proved to be infected based on the lab test result. | Day 1 to Day 365 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) | Rabies Virus Neutralizing Activity (RVNA) was assessed using Rapid Fluorescent Focus Inhibition Test (RFFIT). | Days 4, 15, 43, 99, 183 and 365 | 
| Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL | Rabies Virus Neutralizing Activity (RVNA) was assessed using Rapid Fluorescent Focus Inhibition Test (RFFIT). | Days 4, 8, 15, 43, 99, 183 and 365 | 
| Area Under the Efficacy Curve for the Geometric Mean Concentration (GMC) of Rabies Virus Neutralizing Activity (RVNA) | Rabies Virus Neutralizing Activity (RVNA) was assessed using Rapid Fluorescent Focus Inhibition Test (RFFIT). Area Under the Efficacy Curve for the GMC of RVNA from Study Day 1 to Day 15 after administration (AUEC1-15) | Day 1 to Day 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Post-exposure prophylaxis of Rabies