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

Phase 2

Completed

• Conditions: Rabies
• Interventions: Biological: SYN023; Biological: HRIG (HyperRab); Biological: Rabies vaccine

• Registration Number: NCT03961555
• Lead Sponsor: Synermore Biologics Co., Ltd.

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 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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2019-05-16
• Study First Submitted QC: 2019-05-21
• Study First Posted: 2019-05-23
• Study Start: 2019-09-03
• Primary Completion: 2021-12-23
• Study Completion: 2021-12-23
• Status Verified: 2022-09
• Last Update Submitted: 2022-09-29
• Last Update Posted: 2022-10-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 448

Inclusion Criteria

Not provided

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)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
SYN023+Rabies vaccine	SYN023	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
HRIG+Rabies vaccine	Rabies vaccine	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
SYN023+Rabies vaccine	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 (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
HRIG+Rabies vaccine	HRIG (HyperRab)	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

Primary Outcome Measures

Name	Time	Method
the percentage of subjects with RVNA concentration ≥0.5 IU/mL	D1 and 99	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
geometric mean RVNA concentration (superiority)	Day 1 and 8	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
geometric mean RVNA concentrations at D99	Day 1 and 99	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
cases of probable or confirmed rabie	Day 1, 4, 8, 15, 29, 43, 71, 99, 127, 155, 183, 274 and 365	There are no cases of probable or confirmed rabies in SYN023 recipients

Secondary Outcome Measures

Name	Time	Method
PK for t½ of SYN023 using non-compartmental analysis	Day 1, 4, 8, 15, 99	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
PK for Cl of SYN023 using non-compartmental analysis	Day 1, 4, 8, 15, 99	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
PK for λz of SYN023 using non-compartmental analysis	Day 1, 4, 8, 15, 99	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
The presence and effects of anti-SYN023 antibodies	Day 1, 15, 29, and 99 for LRG group and Day 1, 15 and 99 for NRG group	To evaluate presence and effects of anti-SYN023 antibodies (anti-CTB011, anti-CTB012)
the safety (the number and percentage of adverse events) of SYN023 compared to HRIG	Day 1, 4, 8, 15, 29, 43, 71, 99, 127, 155, 183, 274 and 365	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
geometric mean RVNA concentration on Day 4	Day 1 and 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
geometric mean concentrations of RVNA at each time point	Day 1, 4, 8, 15, 29, 43, 71, 99, 127, 155, 183, 274 and 365	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
PK for Cmax of SYN023 using non-compartmental analysis	Day 1, 4, 8, 15, 99	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
PK for AUC1-t of SYN023 using non-compartmental analysis	Day 1, 4, 8, 15, 99	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
PK for AUC1-inf of SYN023 using non-compartmental analysis	Day 1, 4, 8, 15, 99	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
The ratio of the geometric mean concentrations of RVNA at each time point in geometric mean RVNA AUEC1-15	Day 1, 4, 8, 15, 29, 43, 71, 99, 127, 155, 183, 274 and 365	To demonstrate that the geometric mean RVNA AUEC1-15 for SYN023 is superior to the geometric mean RVNA AUEC1-15 for HRIG
the percentage of RVNA concentration ≥0.5 IU/mL at each time point	Day 1, 4, 8, 15, 29, 43, 71, 99, 127, 155, 183, 274 and 365	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.
PK for Vd of SYN023 using non-compartmental analysis	Day 1, 4, 8, 15, 99	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
PK for Tmax of SYN023 using non-compartmental analysis	Day 1, 4, 8, 15, 99	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
effect of increasing BMI	Day 4, 8, 15, 29, 43, 71, 99, 127, 155, 183, 274 and 365	To describe any effect of increasing BMI on SYN023 and RVNA concentrations

Trial Locations

Locations (14)

University of Florida; 🇺🇸 Gainesville, Florida, United States

University of Iowa; 🇺🇸 Iowa City, Iowa, United States

Baguio General Hospital and Medical Center; 🇵🇭 Baguio City, Benguet, Philippines

Southern Philippines Medical Center; 🇵🇭 Davao City, Davao (Region XI), Philippines

Asian Hospital and Medical Center; 🇵🇭 Muntinlupa, National Capital Region, Philippines

Manila Doctors Hospital Institutional Review Board; 🇵🇭 Manila, Metro Manila, Philippines

Mary Johnston Hospital; 🇵🇭 Manila, Philippines

Research Institute For Tropical Medicine; 🇵🇭 Muntinlupa, National Capital Region, Philippines

Clinical Research Solutions PC -Milan; 🇺🇸 Milan, Tennessee, United States

Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States

University of Virginia; 🇺🇸 Charlottesville, Virginia, United States

De La Salle Health Sciences Institute Independent Ethics Committee; 🇵🇭 Cavite, Calabarzon, Philippines

Center of Excellence in Drug Research, Evaluation and Studies, Inc.; 🇵🇭 Muntinlupa, National Capital Region, Philippines

Far Eastern University Hospital Nicanor Reyes Medical Foundation; 🇵🇭 Quezon City, National Capital Region, Philippines