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

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

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.

Study Overview

• Status: Completed
• Conditions: Rabies
• Intervention / Treatment: Biological: SYN023; Biological: Rabies vaccine; Biological: HRIG (HyperRab)

• Study Type: Interventional
• Enrollment (Actual): 448
• Phase: Phase 2

Contacts and Locations

Study Locations

• Philippines
  • Manila, Philippines
    • Mary Johnston Hospital
  • Benguet
    • Baguio City, Benguet, Philippines, 2600
      • Baguio General Hospital and Medical Center
  • Calabarzon
    • Cavite, Calabarzon, Philippines, 4114
      • De La Salle Health Sciences Institute Independent Ethics Committee
  • Davao (Region XI)
    • Davao City, Davao (Region XI), Philippines, 8000
      • Southern Philippines Medical Center
  • Metro Manila
    • Manila, Metro Manila, Philippines, 1000
      • Manila Doctors Hospital Institutional Review Board
  • National Capital Region
    • Muntinlupa, National Capital Region, Philippines, 1780
      • Asian Hospital and Medical Center
    • Muntinlupa, National Capital Region, Philippines, 1781
      • Center of Excellence in Drug Research, Evaluation and Studies, Inc.
    • Muntinlupa, National Capital Region, Philippines, 1781
      • Research Institute for Tropical Medicine
    • Quezon City, National Capital Region, Philippines, 1118
      • Far Eastern University Hospital Nicanor Reyes Medical Foundation
• United States
  • Florida
    • Gainesville, Florida, United States, 32610
      • University of Florida
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa
  • Tennessee
    • Milan, Tennessee, United States, 38358
      • Clinical Research Solutions PC -Milan
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria (LRG):

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 (Section 3.9.4 and 3.9.5)
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 (NRG)

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 PEP (Section 3.9.4 and 3.9.5)
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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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 (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; it is administered by direct injection into the wound or by subcutaneous or intramuscular injection when this is not possible; Biological: Rabies vaccine; it should be administered in deltoid muscle; Other Names: RabAvert; Rabipur
Active Comparator: HRIG+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	Biological: Rabies vaccine; it should be administered in deltoid muscle; Other Names: RabAvert; Rabipur; Biological: HRIG (HyperRab); it is administered by direct injection into the wound or by subcutaneous or intramuscular injection when this is not possible

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Synermore Biologics Co., Ltd.
• Collaborators: Synermore Biologics USA Limited

Study record dates

Study Major Dates

• Study Start (Actual): September 3, 2019
• Primary Completion (Actual): December 23, 2021
• Study Completion (Actual): December 23, 2021

Study Registration Dates

• First Submitted: May 16, 2019
• First Submitted That Met QC Criteria: May 21, 2019
• First Posted (Actual): May 23, 2019

Study Record Updates

• Last Update Posted (Actual): October 3, 2022
• Last Update Submitted That Met QC Criteria: September 29, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: Post-exposure prophylaxis of Rabies
• Additional Relevant MeSH Terms: RNA Virus Infections; Virus Diseases; Infections; Mononegavirales Infections; Rhabdoviridae Infections; Rabies
• Other Study ID Numbers: SYN023-004

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No