Comparison of SYN023 to Human Rabies Immune Globulin in Post Exposure Prophylaxis of Rabies

Study Overview
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Brief Summary
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This is a Phase 2b, double blinded, randomized study of SYN023 compared to HyperRab® (a licensed Rabies immune globulin from human sources, HRIG) for the prevention of rabies as part of post-exposure prophylaxis (PEP). The trial will enroll sequentially two different risk substrata of WHO Category 3 rabies exposure which are Low Risk Group (LRG) and Normal Risk Group (NRG). The enrollment will be stepwise while subject's data will be reviewed by DSMB to confirm the safety and permit for next enrollment. Besides, rabies vaccine would be administered within 75 minutes 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 the United States.

Official Title
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A Phase 2b Randomized Blinded Study to Evaluate SYN023 Compared to Human Rabies Immune Globulin in Post Exposure Prophylaxis of Rabies in Adults With Different Rabies Exposure Risks

Conditions
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Rabies

Intervention / Treatment
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* Biological: SYN023
* Biological: HRIG (HyperRab)
* Biological: Rabies vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (LRG): Subjects must meet all of the following criteria at the time of subject ID assignment: History of dog, cat, mongoose, fox, ferret, skunk, bat or raccoon bite to trunk, leg, ankle or foot, or lick or scratch with, or of broken skin or mucous membrane saliva or neural tissue contamination, unprotected physical bat contact, scratch or saliva contamination of the head or neck without broken skin all ≤ 54 hours (Section 3.9.4 and 3.9.5) Has completed the written informed consent process and signed informed consent document Males and females Is age equal or more than 18 years on Study Day 1 Agrees to stay in contact with the study site for the duration of the study, provide updated contact information as necessary, and has no current plans to move from the study area for the duration of the study Lives within 2 hour journey by available transportation to study center For female subjects: agrees to avoid pregnancy from Study Day 1 through Study Day 121. Women physically capable of pregnancy (not sterilized and still menstruating or within 1 year of the last menses if menopausal) in sexual relationships with men must use an acceptable method of avoiding pregnancy during this period. Acceptable methods of avoiding pregnancy include a sterile sexual partner, sexual abstinence (not engaging in sexual intercourse), hormonal contraceptives (oral, injection, transdermal patch, or implant), vaginal ring, intrauterine device (IUD), or the combination of a condom or diaphragm with spermicide Inclusion Criteria (NRG) Subjects must meet all of the following criteria at the time of subject ID assignment: History of dog, cat, mongoose, fox, ferret, skunk, bat or raccoon bite to any body part, lick or scratch with, or of broken skin, mucous membrane saliva or neural tissue contamination, or unprotected physical bat contact all ≤ 54 hours from PEP (Section 3.9.4 and 3.9.5) Has completed the written informed consent process and signed informed consent document. Males and females Is age equal or more than 18 years on Study Day 1 Agrees to stay in contact with the study site for the duration of the study, provide updated contact information as necessary, and has no current plans to move from the study area for the duration of the study Lives within 2 hour journey by available transportation to study center For female subjects: agrees to avoid pregnancy from agrees to avoid pregnancy from Study Day 1 through Study Day 121. Women physically capable of pregnancy (not sterilized and still menstruating or within 1 year of the last menses if menopausal) in sexual relationships with men must use an acceptable method of avoiding pregnancy during this period. Acceptable methods of avoiding pregnancy include a sterile sexual partner, sexual abstinence (not engaging in sexual intercourse), hormonal contraceptives (oral, injection, transdermal patch, or implant), vaginal ring, intrauterine device (IUD), or the combination of a condom or diaphragm with spermicide Exclusion Criteria: Subjects must have had none of the following at the time of subject ID assignment: Clinical evidence of rabies infection Category 3 exposure > 54 hours before Study Drug receipt History or serological evidence of previous rabies vaccination Previous receipt of equine or human rabies globulin History of hypersensitivity reaction to equine or human immunoglobulin. Received immunoglobulin or blood products within 42 days before Study Day 1 Received any investigational drug therapy or investigational vaccine within 60 days before Study Day 1 Planned participation in any other investigational study during the study period. Receiving systemic immunosuppressant medication such as systemic corticosteroids but not limited to systemic corticosteroids History or laboratory evidence of any past, present, or possible immunodeficiency state including but not limited to any laboratory indication of HIV infection Previous medical history that may compromise the safety of the subject in the study according to the opinion of the principal investigator History or evidence on physical examination of any systemic disease or any acute or chronic illness that, in the opinion of the investigator, may interfere with the evaluation of the safety or activity of SYN023 Pregnancy (results of the urine pregnancy test MUST be known before enrollment)

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 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 (RabAvert/Rabipur): 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<br>* it is administered by direct injection into the wound or by subcutaneous or intramuscular injection when this is not possible<br>Biological: Rabies vaccine<br>* it should be administered in deltoid muscle<br>* Other names: Rabipur;|
| Active Comparator: HRIG+Rabies vaccine<br>HRIG: Interventions: are administered by direct injection into the wound or by subcutaneous or intramuscular injection when this is not possible Dosage form: 150 IU/mL or 300 IU/mL, liquid, Dosage: 20 IU/kg of HyperRab (HRIG) Frequency/duration: at Day 1 Rabies vaccine (RabAvert/Rabipur): 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 (HyperRab)<br>* it is administered by direct injection into the wound or by subcutaneous or intramuscular injection when this is not possible<br>Biological: Rabies vaccine<br>* it should be administered in deltoid muscle<br>* Other names: Rabipur;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| geometric mean RVNA concentration (superiority) | To demonstrate that the geometric mean RVNA concentration for SYN023 recipients is superior to the geometric mean RVNA concentration for HRIG recipients on Study Day 8 | Day 1 and 8 | 
| geometric mean RVNA concentrations at D99 | To demonstrate that the Study Day 99 geometric mean RVNA concentration for SYN023 recipients is not inferior to the geometric mean RVNA concentration for HRIG recipients | Day 1 and 99 | 
| cases of probable or confirmed rabie | There are no cases of probable or confirmed rabies in SYN023 recipients | Day 1, 4, 8, 15, 29, 43, 71, 99, 127, 155, 183, 274 and 365 | 
| the percentage of subjects with RVNA concentration ≥0.5 IU/mL | To demonstrate that the percentage of subjects with RVNA concentration ≥0.5 IU/mL on Study Day 99 in SYN023 recipients is not inferior to the percentage of recipients with RVNA concentration ≥0.5 IU/mL for HRIG | D1 and 99 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| geometric mean RVNA concentration on Day 4 | To demonstrate that the geometric mean RVNA concentration for SYN023 is superior to the geometric mean RVNA concentration for HRIG on Study Day 4 | Day 1 and 4 | 
| The ratio of the geometric mean concentrations of RVNA at each time point in geometric mean RVNA AUEC1-15 | To demonstrate that the geometric mean RVNA AUEC1-15 for SYN023 is superior to the geometric mean RVNA AUEC1-15 for HRIG | Day 1, 4, 8, 15, 29, 43, 71, 99, 127, 155, 183, 274 and 365 | 
| geometric mean concentrations of RVNA at each time point | To describe the ratio of the geometric mean concentrations of RVNA at each time point in SYN023 recipients divided by the geometric mean concentrations of RVNA in HRIG recipients for LRG and NRG in the per-protocol and as-treated populations | Day 1, 4, 8, 15, 29, 43, 71, 99, 127, 155, 183, 274 and 365 | 
| the percentage of RVNA concentration ≥0.5 IU/mL at each time point | To describe the percentage of RVNA concentration ≥0.5 IU/mL at each time point for SYN023 and HRIG recipients for LRG and NRG in the per-protocol and as-treated populations. | Day 1, 4, 8, 15, 29, 43, 71, 99, 127, 155, 183, 274 and 365 | 
| PK for Vd of SYN023 using non-compartmental analysis | To describe the pharmacokinetics of SYN023 Mab using non-compartmental analysis. Vd will be calculated when possible in the LRG and NRG protocol and as treated populations | Day 1, 4, 8, 15, 99 | 
| PK for Cmax of SYN023 using non-compartmental analysis | To describe the pharmacokinetics of SYN023 Mab using non-compartmental analysis. Cmax will be calculated when possible in the LRG and NRG protocol and as treated populations | Day 1, 4, 8, 15, 99 | 
| PK for Tmax of SYN023 using non-compartmental analysis | To describe the pharmacokinetics of SYN023 Mab using non-compartmental analysis. Tmax will be calculated when possible in the LRG and NRG protocol and as treated populations | Day 1, 4, 8, 15, 99 | 
| PK for AUC1-t of SYN023 using non-compartmental analysis | To describe the pharmacokinetics of SYN023 Mab using non-compartmental analysis. AUC1-t will be calculated when possible in the LRG and NRG protocol and as treated populations | Day 1, 4, 8, 15, 99 | 
| PK for AUC1-inf of SYN023 using non-compartmental analysis | To describe the pharmacokinetics of SYN023 Mab using non-compartmental analysis. AUC1-inf will be calculated when possible in the LRG and NRG protocol and as treated populations | Day 1, 4, 8, 15, 99 | 
| PK for t½ of SYN023 using non-compartmental analysis | To describe the pharmacokinetics of SYN023 Mab using non-compartmental analysis. t½ will be calculated when possible in the LRG and NRG protocol and as treated populations | Day 1, 4, 8, 15, 99 | 
| PK for Cl of SYN023 using non-compartmental analysis | To describe the pharmacokinetics of SYN023 Mab using non-compartmental analysis. Cl will be calculated when possible in the LRG and NRG protocol and as treated populations | Day 1, 4, 8, 15, 99 | 
| PK for λz of SYN023 using non-compartmental analysis | To describe the pharmacokinetics of SYN023 Mab using non-compartmental analysis. λz will be calculated when possible in the LRG and NRG protocol and as treated populations | Day 1, 4, 8, 15, 99 | 
| The presence and effects of anti-SYN023 antibodies | To evaluate presence and effects of anti-SYN023 antibodies (anti-CTB011, anti-CTB012) | Day 1, 15, 29, and 99 for LRG group and Day 1, 15 and 99 for NRG group | 
| the safety (the number and percentage of adverse events) of SYN023 compared to HRIG | To evaluate the safety of SYN023 compared to HyperRab® S/D. The safety profile will be the number and percentage of unsolicited and solicited adverse events recorded at all available post-vaccination time points | Day 1, 4, 8, 15, 29, 43, 71, 99, 127, 155, 183, 274 and 365 | 
| effect of increasing BMI | To describe any effect of increasing BMI on SYN023 and RVNA concentrations | Day 4, 8, 15, 29, 43, 71, 99, 127, 155, 183, 274 and 365 | 

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