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

Primary Purpose

Rabies, Communicable Disease, Virus Diseases

Status

Completed

Phase

Phase 3

Locations

China

Study Type

Interventional

Intervention

SYN023

Human Rabies Immune Globulin (HRIG)

Rabies Vaccine

About this trial

This is an interventional prevention trial for Rabies focused on measuring Post-exposure prophylaxis of Rabies

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Is age 18 years, on Study Day 0 with legal identification documents, and plan to live in the 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;
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 6 months after administration;
Those who have an armpit temperature ≤ 37.0 °C.

Exclusion Criteria:

After inquiry, previous receipt of equine or human (rabies) globulin or rabies vaccination.;
After inquiry, History of bitten by animals, such as dog, cat, mongoose, fox, ferret, skunk, bat or raccoon (with skin damage), within the 6 months before Study Day 0
Category I and Category II rabies exposure ;
History of Category III rabies exposure and received wound suture treatment;
Had fever (armpit temperature ≥ 38.5 °C) within 3 days before Study Day 0, or in the acute episode of any chronic diseases, or received any antipyretic, analgesic or anti-allergic drug within 3 days before enrollment;
After inquiry, history of receiving any immunoglobulin or blood product within 45 days before Study Day 0, or plan to use any such product during the study;
After inquiry, history of receiving systemic immunosuppressive therapy within 45 days before Study Day 0 such as long-term glucocorticoid treatment (period: ≥ 14 days; dosage: ≥ 20 mg /kg/day);
After inquiry, History of any severe congenital defects or autoimmune disease (for example: AIDS, systemic lupus erythematosus, etc.), severe cardiovascular, liver or kidney disorders;
After inquiry, history of asplenia or functional asplenia;
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;
History of any severe neurological disease (Guillain-Barre syndrome, etc.);
History or a family history of convulsion, epilepsy, encephalopathy or mental illness;
After inquiry, Contraindication to intramuscular injection (diagnosed with any coagulopathy or received anticoagulant therapy);
After inquiry, history of receiving any subunit or inactivated vaccine, such as pneumococcal vaccine, within 7 days before Study Day 0;
After inquiry, history of receiving any live attenuated vaccine within 14 days before Study Day 1;
After inquiry, history of addiction to any narcotic, alcohol or drugs;
After inquiry, Previous receipt of any study product (drug, vaccine, biological product or device) within 6 months before Study Day 0, or plan to participate in any other clinical study during this study period;
After inquiry, previous medical history that may affect the evaluation in this trial in the opinion of the investigators.

Sites / Locations

Yunnan Province Center for Disease Control and Prevention (CDC)

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Experimental Group: SYN023+Rabies Vaccine

Control Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine

Arm Description

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

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

Outcomes

Primary Outcome Measures

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).

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.

Secondary Outcome Measures

Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC)

Rabies Virus Neutralizing Activity (RVNA) was assessed using Rapid Fluorescent Focus Inhibition Test (RFFIT).

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).

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)

Full Information

NCT ID

NCT04644484

First Posted

November 16, 2020

Last Updated

March 29, 2023

Sponsor

Synermore Biologics (Suzhou) Co., Ltd.

Collaborators

Simoon Record Pharma Information Consulting Co., Ltd.

1. Study Identification

Unique Protocol Identification Number

NCT04644484

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Completed

Study Start Date

September 23, 2020 (Actual)

Primary Completion Date

June 24, 2022 (Actual)

Study Completion Date

December 16, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Synermore Biologics (Suzhou) Co., Ltd.

Collaborators

Simoon Record Pharma Information Consulting Co., Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

Keywords

Post-exposure prophylaxis of Rabies

7. Study Design

Primary Purpose

Prevention

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

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

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

Blinding for drugs were carried out by the randomization statistician and other personnel who will not be involved in the implementation of the clinical trial. Under the guidance of the randomization statistician, blinding operators attach the printed labels with numbers to the outer packages of the study drug/control drug according to the blind codes and seal the packages with sealing stickers. After the completion of blinding for drugs, the blind codes shall be sealed and kept by the randomization statistician. The entire blinding process must be documented. The personnel responsible for blinding must not participate in other relevant works during this clinical trial, and must not disclose the blind codes to any person participating in this clinical trial.

Allocation

Randomized

Enrollment

1000 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Experimental Group: SYN023+Rabies Vaccine

Arm Type

Experimental

Arm Description

Arm Title

Control Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine

Arm Type

Active Comparator

Arm Description

Intervention Type

Biological

Intervention Name(s)

SYN023

Other Intervention Name(s)

A Humanized Anti-Rabies Molecular antibodies cocktails

Intervention Description

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.

Intervention Type

Biological

Intervention Name(s)

Human Rabies Immune Globulin (HRIG)

Intervention Description

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

Intervention Type

Biological

Intervention Name(s)

Rabies Vaccine

Other Intervention Name(s)

Freeze-dried Rabies Vaccine for Human Use (Vero Cells)

Intervention Description

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

Primary Outcome Measure Information:

Title

Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 8

Description

Rabies Virus Neutralizing Activity (RVNA) was assessed using Rapid Fluorescent Focus Inhibition Test (RFFIT).

Time Frame

Day 8

Title

Number of Probable or Confirmed Rabies Cases

Description

Time Frame

Day 1 to Day 365

Secondary Outcome Measure Information:

Title

Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC)

Description

Rabies Virus Neutralizing Activity (RVNA) was assessed using Rapid Fluorescent Focus Inhibition Test (RFFIT).

Time Frame

Days 4, 15, 43, 99, 183 and 365

Title

Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL

Description

Rabies Virus Neutralizing Activity (RVNA) was assessed using Rapid Fluorescent Focus Inhibition Test (RFFIT).

Time Frame

Days 4, 8, 15, 43, 99, 183 and 365

Title

Area Under the Efficacy Curve for the Geometric Mean Concentration (GMC) of Rabies Virus Neutralizing Activity (RVNA)

Description

Time Frame

Day 1 to Day 15

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Xiaoqiang Liu, MD, PhD

Organizational Affiliation

Yunnan Province CDC

Official's Role

Principal Investigator

Facility Information:

Facility Name

Yunnan Province Center for Disease Control and Prevention (CDC)

City

Kunming

ZIP/Postal Code

650022

Country

China

12. IPD Sharing Statement

Plan to Share IPD

Citations:

PubMed Identifier

34483020

Citation

McClain JB, Chuang A, Reid C, Moore SM, Tsao E. Rabies virus neutralizing activity, pharmacokinetics, and safety of the monoclonal antibody mixture SYN023 in combination with rabies vaccination: Results of a phase 2, randomized, blinded, controlled trial. Vaccine. 2021 Sep 24;39(40):5822-5830. doi: 10.1016/j.vaccine.2021.08.066. Epub 2021 Sep 3.

Results Reference

result

PubMed Identifier

33091433

Citation

Ding Y, Wu M, Zhang H, Zhu X, Hu Y, Li X, Liu J, Tsao E, Liu M, Li C. Safety, pharmacokinetics and pharmacodynamics of SYN023 alone or in combination with a rabies vaccine: An open, parallel, single dose, phase 1 bridging study in healthy Chinese subjects. Antiviral Res. 2020 Dec;184:104956. doi: 10.1016/j.antiviral.2020.104956. Epub 2020 Oct 19.

Results Reference

result

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

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