Rabies, Communicable Disease, Virus Diseases, Rhabdoviridae Infections, Mononegavirales Infections, RNA Virus Infections
Conditions
Keywords
Post-exposure prophylaxis of Rabies
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.
Interventions
BIOLOGICALSYN023
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.
BIOLOGICALHuman Rabies Immune Globulin (HRIG)
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
BIOLOGICALRabies Vaccine
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
Sponsors
Simoon Record Pharma Information Consulting Co., Ltd.
Synermore Biologics (Suzhou) Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes 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.
Intervention 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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Is age ≥18 years, on Study Day 1 with legal identification documents, and plan to live in the local administration area during the study; 2. Category III rabies exposure within 24 hours before Study Drug receipt ; 3. Completed written informed consent process, and signed the informed consent forms; 4. Subjects with the ability to understand the study procedure. And agreed to complete all follow-ups; 5. 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; 6. Those who have an armpit temperature ≤ 37.0 °C.
Exclusion criteria
1. Previous receipt of equine or human (rabies) globulin or rabies vaccination prior to randomization; 2. Clinical evidence of rabies infection; 3. Category I and Category II rabies exposure; 4. Had fever (armpit temperature ≥ 38.5 °C) within 3 days before Study Day 1, or in the acute episode of any chronic diseases; 5. 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; 6. Received systemic immunosuppressant medication such as systemic corticosteroids but not limited to systemic corticosteroids within 43 days before Study Day 1; 7. 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; 8. History of spleen function deficiency or function injury, such as no spleen caused by any cause (such as splenectomy); 9. 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; 10. 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; 11. 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; 12. Previous medical history that may compromise the safety of the subject in the study according to the opinion of the principal investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 8 | Day 8 | Rabies Virus Neutralizing Activity (RVNA) was assessed using Rapid Fluorescent Focus Inhibition Test (RFFIT). |
| Number of Probable or Confirmed Rabies Cases | Day 1 to Day 365 | WHO's Classification of Rabies Cases: 1. Suspected case: refers to a case that satisfies the definition of clinical case; 2. Probable case: refers to a suspected case with a reliable medical history of contact with any suspected animal infected with the rabies virus; 3. Confirmed case: refers to a suspected or probable case that is proved to be infected based on the lab test result. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) | Days 4, 15, 43, 99, 183 and 365 | 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 | Days 4, 8, 15, 43, 99, 183 and 365 | 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) | Day 1 to Day 15 | 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) |
Countries
China
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Experimental Group: SYN023+Rabies Vaccine 1000 patients aged 18 and above with 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 post-exposure prophylaxis (PEP).
SYN023: 0.3 mg/kg, wound infiltration injection. If the study drug isn't used up after infiltration injection for all wounds, the remaining amount should be injected into the muscles far away from the vaccine injection sites Frequency/duration: at Day 1
Rabies Vaccine: 0.5 milliliters (mL), intramuscular injection into the deltoid muscle Frequency/duration: at Day 1, 4, 8, 15, 29 | 750 |
| Control Group: Human Rabies Immune Globulin (HRIG)+Rabie Vaccine 1000 patients aged 18 and above with 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 post-exposure prophylaxis (PEP).
Human Rabies Immune Globulin (HRIG): 20 IU/kg, wound infiltration injection. If the study drug isn't used up after infiltration injection for all wounds, the remaining amount should be injected into the muscles far away from the vaccine injection sites Frequency/duration: at Day 1
Rabies Vaccine: 0.5 milliliters (mL), intramuscular injection into the deltoid muscle Frequency/duration: at Day 1, 4, 8, 15, 29 | 250 |
| Total | 1,000 |
Baseline characteristics
| Characteristic | Experimental Group: SYN023+Rabies Vaccine | Control Group: Human Rabies Immune Globulin (HRIG)+Rabie Vaccine | Total |
|---|---|---|---|
| Age, Continuous | 43.7 years | 44.6 years | 43.9 years |
| BMI | 23.39 kg/m^2 STANDARD_DEVIATION 3.489 | 24.12 kg/m^2 STANDARD_DEVIATION 3.786 | 23.57 kg/m^2 STANDARD_DEVIATION 3.578 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 750 Participants | 250 Participants | 1000 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 346 Participants | 117 Participants | 463 Participants |
| Sex: Female, Male Male | 404 Participants | 133 Participants | 537 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 750 | 0 / 250 |
| other Total, other adverse events | 315 / 750 | 138 / 250 |
| serious Total, serious adverse events | 41 / 750 | 14 / 250 |
Outcome results
Primary
Number of Probable or Confirmed Rabies Cases
WHO's Classification of Rabies Cases: 1. Suspected case: refers to a case that satisfies the definition of clinical case; 2. Probable case: refers to a suspected case with a reliable medical history of contact with any suspected animal infected with the rabies virus; 3. Confirmed case: refers to a suspected or probable case that is proved to be infected based on the lab test result.
Time frame: Day 1 to Day 365
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental Group: SYN023+Rabies Vaccine | Number of Probable or Confirmed Rabies Cases | 0 participants |
| Control Group: Human Rabies Immune Globulin (HRIG)+Rabie Vaccine | Number of Probable or Confirmed Rabies Cases | 0 participants |
Primary
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).
Time frame: Day 8
Population: The primary analysis set of the outcome measure data is Per-Protocol Analysis Set (PPS). The PPS included all subjects who were randomized, received the correct study drug, passed the confirmation of the inclusion/exclusion criteria \*, completed the rabies vaccination schedule as required by the protocol on Day 29 of the study, had no major protocol violations impacting efficacy evaluation, received adequate wound treatment of all exposed sites, and received study drug injection.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Experimental Group: SYN023+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 8 | 4.346 IU/mL |
| Control Group: Human Rabies Immune Globulin (HRIG)+Rabie Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 8 | 0.232 IU/mL |
Secondary
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)
Time frame: Day 1 to Day 15
Population: The Per Protocol Set (PPS) included all subjects who were randomized, received the correct study drug, passed the confirmation of the inclusion/exclusion criteria \*, completed the rabies vaccination schedule as required by the protocol on Day 29 of the study, had no major protocol violations impacting efficacy evaluation, received adequate wound treatment of all exposed sites, and received study drug injection.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Experimental Group: SYN023+Rabies Vaccine | Area Under the Efficacy Curve for the Geometric Mean Concentration (GMC) of Rabies Virus Neutralizing Activity (RVNA) | 96.972 days *IU/mL |
| Control Group: Human Rabies Immune Globulin (HRIG)+Rabie Vaccine | Area Under the Efficacy Curve for the Geometric Mean Concentration (GMC) of Rabies Virus Neutralizing Activity (RVNA) | 31.869 days *IU/mL |
Secondary
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).
Time frame: Days 4, 8, 15, 43, 99, 183 and 365
Population: The analysis set of the outcome measure data is Per-Protocol Analysis Set (PPS). The PPS included all subjects who were randomized, received the correct study drug, passed the confirmation of the inclusion/exclusion criteria \*, completed the rabies vaccination schedule as required by the protocol on Day 29 of the study, had no major protocol violations impacting efficacy evaluation, received adequate wound treatment of all exposed sites, and received study drug injection.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Experimental Group: SYN023+Rabies Vaccine | Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL | Day 43 | 100 percentage of participants(%) |
| Experimental Group: SYN023+Rabies Vaccine | Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL | Day 4 | 99.8 percentage of participants(%) |
| Experimental Group: SYN023+Rabies Vaccine | Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL | Day 99 | 97.8 percentage of participants(%) |
| Experimental Group: SYN023+Rabies Vaccine | Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL | Day 15 | 100 percentage of participants(%) |
| Experimental Group: SYN023+Rabies Vaccine | Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL | Day 183 | 72.8 percentage of participants(%) |
| Experimental Group: SYN023+Rabies Vaccine | Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL | Day 365 | 47.2 percentage of participants(%) |
| Experimental Group: SYN023+Rabies Vaccine | Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL | Day 8 | 99.6 percentage of participants(%) |
| Control Group: Human Rabies Immune Globulin (HRIG)+Rabie Vaccine | Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL | Day 365 | 81.9 percentage of participants(%) |
| Control Group: Human Rabies Immune Globulin (HRIG)+Rabie Vaccine | Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL | Day 4 | 9.1 percentage of participants(%) |
| Control Group: Human Rabies Immune Globulin (HRIG)+Rabie Vaccine | Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL | Day 8 | 17.6 percentage of participants(%) |
| Control Group: Human Rabies Immune Globulin (HRIG)+Rabie Vaccine | Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL | Day 15 | 96.4 percentage of participants(%) |
| Control Group: Human Rabies Immune Globulin (HRIG)+Rabie Vaccine | Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL | Day 43 | 99.4 percentage of participants(%) |
| Control Group: Human Rabies Immune Globulin (HRIG)+Rabie Vaccine | Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL | Day 99 | 97.5 percentage of participants(%) |
| Control Group: Human Rabies Immune Globulin (HRIG)+Rabie Vaccine | Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL | Day 183 | 95.6 percentage of participants(%) |
Secondary
Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC)
Rabies Virus Neutralizing Activity (RVNA) was assessed using Rapid Fluorescent Focus Inhibition Test (RFFIT).
Time frame: Days 4, 15, 43, 99, 183 and 365
Population: The analysis set of the outcome measure data is Per-Protocol Analysis Set (PPS). The PPS included all subjects who were randomized, received the correct study drug, passed the confirmation of the inclusion/exclusion criteria \*, completed the rabies vaccination schedule as required by the protocol on Day 29 of the study, had no major protocol violations impacting efficacy evaluation, received adequate wound treatment of all exposed sites, and received study drug injection.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Experimental Group: SYN023+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) | Day 4 | 4.212 IU/mL |
| Experimental Group: SYN023+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) | Day 15 | 13.590 IU/mL |
| Experimental Group: SYN023+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) | Day 43 | 13.084 IU/mL |
| Experimental Group: SYN023+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) | Day 99 | 2.023 IU/mL |
| Experimental Group: SYN023+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) | Day 183 | 0.891 IU/mL |
| Experimental Group: SYN023+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) | Day 365 | 0.520 IU/mL |
| Control Group: Human Rabies Immune Globulin (HRIG)+Rabie Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) | Day 183 | 3.319 IU/mL |
| Control Group: Human Rabies Immune Globulin (HRIG)+Rabie Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) | Day 4 | 0.193 IU/mL |
| Control Group: Human Rabies Immune Globulin (HRIG)+Rabie Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) | Day 99 | 5.108 IU/mL |
| Control Group: Human Rabies Immune Globulin (HRIG)+Rabie Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) | Day 15 | 7.651 IU/mL |
| Control Group: Human Rabies Immune Globulin (HRIG)+Rabie Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) | Day 365 | 1.645 IU/mL |
| Control Group: Human Rabies Immune Globulin (HRIG)+Rabie Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) | Day 43 | 16.003 IU/mL |