Rabies
Conditions
Keywords
Post-exposure prophylaxis of Rabies
Brief summary
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 data and safety monitoring board (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.
Interventions
BIOLOGICALSYN023
it is administered by direct injection into the wound or by subcutaneous or intramuscular injection when this is not possible
BIOLOGICALHRIG (HyperRab)
it is administered by direct injection into the wound or by subcutaneous or intramuscular injection when this is not possible
BIOLOGICALRabies vaccine
it should be administered in deltoid muscle
Sponsors
Synermore Biologics USA Limited
Synermore Biologics Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
(Low Risk Group): Subjects must meet all of the following criteria at the time of subject ID assignment: 1. 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 2. Has completed the written informed consent process and signed informed consent document 3. Males and females 4. Is age equal or more than 18 years on Study Day 1 5. 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 6. Lives within 2 hour journey by available transportation to study center 7. 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 (Normal Risk Group) Subjects must meet all of the following criteria at the time of subject ID assignment: 1. 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 post exposure prophylaxis (PEP) 2. Has completed the written informed consent process and signed informed consent document. 3. Males and females 4. Is age equal or more than 18 years on Study Day 1 5. 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 6. Lives within 2 hour journey by available transportation to study center 7. 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: 1. Clinical evidence of rabies infection 2. Category 3 exposure \> 54 hours before Study Drug receipt 3. History or serological evidence of previous rabies vaccination 4. Previous receipt of equine or human rabies globulin 5. History of hypersensitivity reaction to equine or human immunoglobulin. 6. Received immunoglobulin or blood products within 42 days before Study Day 1 7. Received any investigational drug therapy or investigational vaccine within 60 days before Study Day 1 8. Planned participation in any other investigational study during the study period. 9. Receiving systemic immunosuppressant medication such as systemic corticosteroids but not limited to systemic corticosteroids 10. History or laboratory evidence of any past, present, or possible immunodeficiency state including but not limited to any laboratory indication of HIV infection 11. Previous medical history that may compromise the safety of the subject in the study according to the opinion of the principal investigator 12. 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 13. Pregnancy (results of the urine pregnancy test MUST be known before enrollment)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Probable or Confirmed Rabies Cases | Day 1 to Day 365 | Case Classification Human Rabies * Suspected: A case that is compatible with the clinical case definition * Probable: A suspected case (above) plus history of contact with a suspected rabid animal. * Confirmed: A suspected case that is laboratory-confirmed. |
| 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). |
| Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 99 | Day 99 | 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 at Study Day 99 | Day 99 | Rabies Virus Neutralizing Activity (RVNA) was assessed using Rapid Fluorescent Focus Inhibition Test (RFFIT). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 4 | Day 4 | 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) |
| Maximum Observed Serum Concentration (Cmax) | Day 1 to Day 99 | The Cmax of CTB011 and CTB012 derived from non-compartmental analysis. |
| Time of Maximum Observed Serum Concentration (Tmax) | Day 1 to Day 99 | The Tmax of CTB011 and CTB012 derived from non-compartmental analysis. |
Countries
Philippines, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Low Risk Group: SYN023+Rabies Vaccine This includes all participants in the Low Risk Group (LRG) receiving SYN023+Rabies Vaccine. | 45 |
| Low Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine This includes all participants in the Low Risk Group (LRG) receiving Human Rabies Immune Globulin (HRIG)+Rabies Vaccine. | 35 |
| Normal Risk Group: SYN023+Rabies Vaccine This includes all participants in the Normal Risk Group (NRG) receiving SYN023+Rabies Vaccine. | 183 |
| Normal Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine This includes all participants in the Normal Risk Group (NRG) receiving Human Rabies Immune Globulin (HRIG)+Rabies Vaccine. | 184 |
| Total | 447 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Death | 0 | 1 | 0 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | No treatment received | 0 | 0 | 1 | 0 |
| Overall Study | Other | 0 | 0 | 2 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 | 4 |
Baseline characteristics
| Characteristic | Low Risk Group: SYN023+Rabies Vaccine | Low Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine | Normal Risk Group: SYN023+Rabies Vaccine | Normal Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine | Total |
|---|---|---|---|---|---|
| Age, Continuous | 38.0 years STANDARD_DEVIATION 14.26 | 38.4 years STANDARD_DEVIATION 13.73 | 31.9 years STANDARD_DEVIATION 11.33 | 31.3 years STANDARD_DEVIATION 12.49 | 34.9 years STANDARD_DEVIATION 12.95 |
| BMI | 24.70 kg/m^2 STANDARD_DEVIATION 4.612 | 23.66 kg/m^2 STANDARD_DEVIATION 4.732 | 23.89 kg/m^2 STANDARD_DEVIATION 4.787 | 23.69 kg/m^2 STANDARD_DEVIATION 4.573 | 24.25 kg/m^2 STANDARD_DEVIATION 4.664 |
| Race/Ethnicity, Customized Asian | 45 Participants | 35 Participants | 183 Participants | 184 Participants | 447 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 45 Participants | 35 Participants | 183 Participants | 182 Participants | 445 Participants |
| Region of Enrollment Philippines | 45 participants | 35 participants | 183 participants | 184 participants | 447 participants |
| Sex: Female, Male Female | 24 Participants | 18 Participants | 85 Participants | 84 Participants | 211 Participants |
| Sex: Female, Male Male | 21 Participants | 17 Participants | 98 Participants | 100 Participants | 236 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 45 | 1 / 35 | 0 / 183 | 0 / 184 |
| other Total, other adverse events | 9 / 45 | 11 / 35 | 40 / 183 | 30 / 184 |
| serious Total, serious adverse events | 0 / 45 | 1 / 35 | 1 / 183 | 2 / 184 |
Outcome results
Primary
Number of Probable or Confirmed Rabies Cases
Case Classification Human Rabies * Suspected: A case that is compatible with the clinical case definition * Probable: A suspected case (above) plus history of contact with a suspected rabid animal. * Confirmed: A suspected case that is laboratory-confirmed.
Time frame: Day 1 to Day 365
Population: The primary efficacy analyses were performed and summarized for the for the Normal Risk Group per-protocol population. Results for the Low Risk Group per-protocol population are only presented in-text tables. Per-protocol population: all subjects who were randomly assigned, received the correct study drug, met inclusion/exclusion criteria, completed all rabies scheduled vaccinations, lacked major protocol deviations, had adequate wound treatment and study drug injection of all exposure sites.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Low Risk Group: SYN023+Rabies Vaccine | Number of Probable or Confirmed Rabies Cases | 0 participants |
| Low Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine | Number of Probable or Confirmed Rabies Cases | 0 participants |
| Normal Risk Group: SYN023+Rabies Vaccine | Number of Probable or Confirmed Rabies Cases | 0 participants |
| Normal Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine | Number of Probable or Confirmed Rabies Cases | 0 participants |
Primary
Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL at Study Day 99
Rabies Virus Neutralizing Activity (RVNA) was assessed using Rapid Fluorescent Focus Inhibition Test (RFFIT).
Time frame: Day 99
Population: The primary efficacy analyses were performed and summarized for the for the Normal Risk Group per-protocol population. Results for the Low Risk Group per-protocol population are only presented in-text tables. Per-protocol population: all subjects who were randomly assigned, received the correct study drug, met inclusion/exclusion criteria, completed all rabies scheduled vaccinations, lacked major protocol deviations, had adequate wound treatment and study drug injection of all exposure sites.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Low Risk Group: SYN023+Rabies Vaccine | Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL at Study Day 99 | 30 Participants |
| Low Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine | Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL at Study Day 99 | 28 Participants |
| Normal Risk Group: SYN023+Rabies Vaccine | Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL at Study Day 99 | 138 Participants |
| Normal Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine | Percentage of Participants With Rabies Virus Neutralizing Activity (RVNA) ≥0.5 IU/mL at Study Day 99 | 142 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 efficacy analyses were performed and summarized for the for the Normal Risk Group per-protocol population. Results for the Low Risk Group per-protocol population are only presented in-text tables. The per-protocol population included all as-treated subjects without any major protocol deviation who had met all inclusion/exclusion criteria and received complete study treatment.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Low Risk Group: SYN023+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 8 | 4.70 IU/mL | Geometric Coefficient of Variation 0.37 |
| Low Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 8 | 0.13 IU/mL | Geometric Coefficient of Variation 0.1 |
| Normal Risk Group: SYN023+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 8 | 3.30 IU/mL | Geometric Coefficient of Variation 0.61 |
| Normal Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 8 | 0.17 IU/mL | Geometric Coefficient of Variation 1.39 |
Primary
Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 99
Rabies Virus Neutralizing Activity (RVNA) was assessed using Rapid Fluorescent Focus Inhibition Test (RFFIT).
Time frame: Day 99
Population: The primary efficacy analyses were performed and summarized for the for the Normal Risk Group per-protocol population. Results for the Low Risk Group per-protocol population are only presented in-text tables. Per-protocol population: all subjects who were randomly assigned, received the correct study drug, met inclusion/exclusion criteria, completed all rabies scheduled vaccinations, lacked major protocol deviations, had adequate wound treatment and study drug injection of all exposure sites.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Low Risk Group: SYN023+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 99 | 0.66 IU/mL | Geometric Coefficient of Variation 1.13 |
| Low Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 99 | 1.72 IU/mL | Geometric Coefficient of Variation 1.83 |
| Normal Risk Group: SYN023+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 99 | 0.97 IU/mL | Geometric Coefficient of Variation 1.21 |
| Normal Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 99 | 1.47 IU/mL | Geometric Coefficient of Variation 1.6 |
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 secondary efficacy analyses were performed and summarized for the for the Normal Risk Group per-protocol population. Results for the Low Risk Group per-protocol population are only presented in-text tables. Per-protocol population: all subjects who were randomly assigned, received the correct study drug, met inclusion/exclusion criteria, completed all rabies scheduled vaccinations, lacked major protocol deviations, had adequate wound treatment and study drug injection of all exposure sites.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Low Risk Group: SYN023+Rabies Vaccine | Area Under the Efficacy Curve for the Geometric Mean Concentration (GMC) of Rabies Virus Neutralizing Activity (RVNA) | 42.91 day.IU/mL | Geometric Coefficient of Variation 0.44 |
| Low Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine | Area Under the Efficacy Curve for the Geometric Mean Concentration (GMC) of Rabies Virus Neutralizing Activity (RVNA) | 5.79 day.IU/mL | Geometric Coefficient of Variation 1.43 |
| Normal Risk Group: SYN023+Rabies Vaccine | Area Under the Efficacy Curve for the Geometric Mean Concentration (GMC) of Rabies Virus Neutralizing Activity (RVNA) | 46.00 day.IU/mL | Geometric Coefficient of Variation 0.57 |
| Normal Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine | Area Under the Efficacy Curve for the Geometric Mean Concentration (GMC) of Rabies Virus Neutralizing Activity (RVNA) | 9.81 day.IU/mL | Geometric Coefficient of Variation 2.29 |
Secondary
Maximum Observed Serum Concentration (Cmax)
The Cmax of CTB011 and CTB012 derived from non-compartmental analysis.
Time frame: Day 1 to Day 99
Population: The pharmacokinetics of SYN023 was analyzed in the LRG and NRG per-protocol population. No detectable and quantifiable levels of CTB011 and CTB012 were observed in human rabies immune globulin groups, so no PK or statistical analysis was planned.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Low Risk Group: SYN023+Rabies Vaccine | Maximum Observed Serum Concentration (Cmax) | Cmax for CTB011 | 903 ng/mL | Geometric Coefficient of Variation 23.8 |
| Low Risk Group: SYN023+Rabies Vaccine | Maximum Observed Serum Concentration (Cmax) | Cmax for CTB012 | 916.5 ng/mL | Geometric Coefficient of Variation 31.3 |
| Low Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine | Maximum Observed Serum Concentration (Cmax) | Cmax for CTB011 | 700 ng/mL | Geometric Coefficient of Variation 25.9 |
| Low Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine | Maximum Observed Serum Concentration (Cmax) | Cmax for CTB012 | 628 ng/mL | Geometric Coefficient of Variation 32.6 |
Secondary
Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 4
Rabies Virus Neutralizing Activity (RVNA) was assessed using Rapid Fluorescent Focus Inhibition Test (RFFIT).
Time frame: Day 4
Population: The secondary efficacy analyses were performed and summarized for the for the Normal Risk Group per-protocol population. Results for the Low Risk Group per-protocol population are only presented in-text tables. Per-protocol population: all subjects who were randomly assigned, received the correct study drug, met inclusion/exclusion criteria, completed all rabies scheduled vaccinations, lacked major protocol deviations, had adequate wound treatment and study drug injection of all exposure sites.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Low Risk Group: SYN023+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 4 | 3.30 IU/mL | Geometric Coefficient of Variation 1.27 |
| Low Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 4 | 0.12 IU/mL | Geometric Coefficient of Variation 0.36 |
| Normal Risk Group: SYN023+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 4 | 3.30 IU/mL | Geometric Coefficient of Variation 0.6 |
| Normal Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine | Rabies Virus Neutralizing Activity (RVNA) of Geometric Mean Concentration (GMC) at Study Day 4 | 0.14 IU/mL | Geometric Coefficient of Variation 0.82 |
Secondary
Time of Maximum Observed Serum Concentration (Tmax)
The Tmax of CTB011 and CTB012 derived from non-compartmental analysis.
Time frame: Day 1 to Day 99
Population: The pharmacokinetics of SYN023 was analyzed in the LRG and NRG per-protocol population. No detectable and quantifiable levels of CTB011 and CTB012 were observed in human rabies immune globulin groups, so no PK or statistical analysis was planned.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Low Risk Group: SYN023+Rabies Vaccine | Time of Maximum Observed Serum Concentration (Tmax) | Tmax for CTB011 | 2.93 day | Full Range 0.23 |
| Low Risk Group: SYN023+Rabies Vaccine | Time of Maximum Observed Serum Concentration (Tmax) | Tmax for CTB012 | 2.87 day | Full Range 0.34 |
| Low Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine | Time of Maximum Observed Serum Concentration (Tmax) | Tmax for CTB011 | 2.89 day | Full Range 0.34 |
| Low Risk Group: Human Rabies Immune Globulin (HRIG)+Rabies Vaccine | Time of Maximum Observed Serum Concentration (Tmax) | Tmax for CTB012 | 2.89 day | Full Range 0.34 |