A Phase III Clinical Study to Evaluate SYN023's Efficacy and Safety
Study Details
Study Description
Brief Summary
This is a Phase III, blinded, randomized study of SYN023 compared to a China licensed Human Rabies Immunoglbulin (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 WHO Category 3 rabies exposure subjects. The subject's death and rabies data will be reviewed by 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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
This is a Phase Ⅲ, 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 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 0 (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 3, 7, 14, and 28 respectively.
3.0 mL of venous blood samples should be collected 8 times from each subject prior to administration and on Study Day 3, 7, 14, 42, 98, 182, and 364 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 42 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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Experimental Group: SYN023+Rabies Vaccine 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 1mL before use Dosage: 1 mL after reconstitution Frequency/duration: at Day 1, 4, 8, 15, 29 |
Biological: SYN023
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 mAb. The glass bottle was closed with a 13 mm bromobutyl rubber stopper, a 13 mm aluminum crimping cap and a polypropylene flip-open lid.
Other Names:
Biological: Rabies 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 mL before use Dosage: 0.5 mL after reconstitution Frequency/duration: at Day 1, 4, 8, 15, 29
Other Names:
|
| Active Comparator: Control Group: HRIG+Rabie Vaccine 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 1mL before use Dosage: 1 mL after reconstitution Frequency/duration: at Day 1, 4, 8, 15, 29 |
Biological: 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
Other Names:
Biological: Rabies 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 mL before use Dosage: 0.5 mL after reconstitution Frequency/duration: at Day 1, 4, 8, 15, 29
Other Names:
|
Outcome Measures
Primary Outcome Measures
- To demonstrate the Geometric mean RVNA Concentration for SYN023 recipients is superior to the geometric mean RVNA concentration for HRIG recipients on Study Day 8, AND [8 days]
RVNA (Rabies Virus Neutralisation Assay) geometric mean concentration of SYN023 recipients and HRIG recipients
- To demonstrate there are no probable or confirmed case of rabies [365 days]
To demonstrate there are no case of rabies
Secondary Outcome Measures
- To evaluate the safety of SYN023 compared to HRIG within 98 days and 1 year after administration; [365 days]
To assess the safey of SYN023 and HRIG according to the U.S. FDA guideline and Chinese guideline
- To demonstrate the Geometric mean RVNA Concentration for SYN023 recipients is superior to the geometric mean RVNA concentration for HRIG recipients on Study Day 4 [4 days]
RVNA (Rabies Virus Neutralisation Assay) geometric mean concentration of SYN023 recipients and HRIG recipients
- To demonstrate that the geometric mean RVNA AUEC1-15 for SYN023 is superior to the geometric mean RVNA AUEC1-15 for HRIG [15 days]
To assess the geometric mean RVNA AUEC1-15 for SYN023 and HRIG recipients
- To demonstrate that the percentage of subjects with RVNA concentration ≥ 0.5 IU/mL on Study Day 15 in SYN023 recipients is not inferior to the percentage of recipients with RVNA concentration ≥ 0.5 IU/mL for HRIG [15 days]
To assess the RVNA concentration ≥ 0.5 IU/mL on Study Day 15 in SYN023 and HRIG recipients
- To demonstrate that the percentage of subjects with RVNA concentration ≥ 0.5 IU/mL on Study Day 15 in SYN023 recipients is not inferior to the percentage of recipients with RVNA concentration ≥ 0.5 IU/mL for HRIG [365 days]
To assess the RVNA concentration ≥ 0.5 IU/mL on Study Day 15 in SYN023 and HRIG recipients
- To describe the percentage of RVNA concentration ≥ 0.5 IU/mL at each time point for SYN023 and HRIG recipients [365 days]
To assess the RVNA concentration ≥ 0.5 IU/mL on each following up time point
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Is age 18 years, on Study Day 0 with legal identification documents, and plan to live in the area during the study;
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Category III rabies exposure within 24 hours before Study Drug receipt ;
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Completed written informed consent process, and signed the informed consent forms;
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Agreed to complete all follow-ups;
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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;
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Those who have an armpit temperature ≤ 37.0 °C.
Exclusion Criteria:
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After inquiry, previous receipt of equine or human (rabies) globulin or rabies vaccination.;
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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
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Category I and Category II rabies exposure ;
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History of Category III rabies exposure and received wound suture treatment;
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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;
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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;
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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);
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After inquiry, History of any severe congenital defects or autoimmune disease (for example: AIDS, systemic lupus erythematosus, etc.), severe cardiovascular, liver or kidney disorders;
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After inquiry, history of asplenia or functional asplenia;
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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;
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History of any severe neurological disease (Guillain-Barre syndrome, etc.);
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History or a family history of convulsion, epilepsy, encephalopathy or mental illness;
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After inquiry, Contraindication to intramuscular injection (diagnosed with any coagulopathy or received anticoagulant therapy);
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After inquiry, history of receiving any subunit or inactivated vaccine, such as pneumococcal vaccine, within 7 days before Study Day 0;
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After inquiry, history of receiving any live attenuated vaccine within 14 days before Study Day 1;
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After inquiry, history of addiction to any narcotic, alcohol or drugs;
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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;
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After inquiry, previous medical history that may affect the evaluation in this trial in the opinion of the investigators.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Yunnan Province Center for Disease Control and Prevention (CDC) | Kunming | China | 650022 |
Sponsors and Collaborators
- Synermore Biologics (Suzhou) Co., Ltd.
- Simoon Record Pharma Information Consulting Co., Ltd.
- Clinchoice Inc
Investigators
- Principal Investigator: Xiaoqiang Liu, MD, PhD, Yunnan Province CDC
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- SYN023-006