A Comparison of the Safety, PD and PK of a Single Dose of SYN023 Administered With Licensed Rabies Vaccines

Study Overview
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Brief Summary
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This is single site, randomized, blinded comparison of the immunogenicity, of Imovax (RVi) and Rabavert (RVa) rabies vaccines when subjects are administered rabies immune globulin (RIG) or SYN023. Subjects will be randomized into one of four dose groups: RVi + SYN023, RVi+RIG, RVa+SYN023 and RVa+RIG. The initial dose of RVi and RVa will be co-administered with either RIG or SYN023). Rabies virus neutralizing activity (RVNA) and blood levels of SYN023 will be measured for the remainder of the trial while the rest of the five RVi and RVa doses are given. The study will last 112 days. SYN023 concentrations and anti-SYN023 antibodies will also be measured.

Detailed Description
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Administered immunoglobulins directed against vaccine antigens have the potential to inhibit the immune response to a vaccine. Both vaccination and immune globulin are used together in the post exposure prophylaxis of rabies virus infection. SYN023 (a mixture of two monoclonal antibodies CTB011 and CTB012) may be used instead of human rabies immune globulin. Since there is a risk of antagonism of vaccine induced immunity by SYN023, as there is with rabies immune globulin, it is necessary to study possible interactions of these two agents that might be used concurrently. This is single site, randomized, blinded comparison of the immunogenicity, of Imovax (RVi) and Rabavert (RVa) rabies vaccines when administered concurrently with rabies immune globulin (RIG) or SYN023. Subjects will be randomized into one of four dose groups: RVi + SYN023, RVi + RIG, RVa+SYN023 and RVa + RIG. The initial dose of RVi and RVa will be co-administered with either RIG or SYN023). The remaining 4 doses of RVi and RVa will be administered intramuscularly as specified in the product labeling. Serum rabies virus neutralizing activity (RVNA) and serum concentrations of the components of of SYN023 will be measured for the remainder of the trial while the rest of the five RVi and RVa doses are given. Adverse events will be collected for the duration of the trial. The study will last 112 days. Anti-SYN023 antibodies will also be measured.

Official Title
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A Phase 2 Randomized Blinded Placebo Controlled Comparison of the Safety Pharmacokinetics and Pharmacodynamics of a Single Dose of SYN023 Administered With Licensed Rabies Vaccines in Healthy Adult Subjects

Conditions
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Human Rabies

Intervention / Treatment
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* Biological: SYN023
* Biological: Imovax
* Biological: RabAvert
* Biological: HyperRAB ST (human rabies immune globulin)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects between 18 and 50 years of age, inclusive Body mass index between 18 and 30 kg/m², inclusive Female subjects physically capable of pregnancy (i.e., not sterilized and still menstruating or within 1 year of the last menses if menopausal) must: Agree to avoid pregnancy from 28 days prior to Study Day 0 through the duration of the study. If in a sexual relationship with a man, use an acceptable method of avoiding pregnancy during this period. Acceptable methods of avoiding pregnancy include: the use of at least two forms of contraception, including use by a partner of a barrier method (e.g., male condom with intravaginal spermicide) as one form of contraception. Women of childbearing potential must have a negative serum pregnancy test within 24 hours preceding receipt of each dose. Can understand and sign the informed consent document, can communicate with the investigator and provide updated contact information as needed for the duration of the study, has no current plans to move from the study area for the duration of the study, and can understand and comply with the requirements of the protocol. Exclusion Criteria: Oral temperature ≥37.5°C at screening Complete blood count (CBC) and platelet count abnormal values (>5% above the upper limit of normal [ULN] or >5% below the lower limit of normal [LLN] per local laboratory parameters) at screening with exception of absolute lymphocyte count. Abnormally elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, alkaline phosphatase (ALP), or creatinine (Cr) values at screening (however a single test AST, ALT or ALP may be >10% above the ULN per local laboratory parameters) Abnormal PT (INR) PTT Abnormal screening urinalysis result that is, per the investigator, clinically significant, or a screening urine dipstick result of ≥2+ protein Positive screening urine test for illicit drugs (opiates, cocaine, amphetamines methamphetamines, barbiturates, benzodiazepines, tetrahydrocannabinol, PCP, MDMA, and methadone) History or evidence of autoimmune disease History or evidence of any past, present, or future possible immunodeficiency state, including laboratory evidence of human immunodeficiency virus (HIV) 1 or 2 infection History or evidence of chronic hepatitis History or evidence of rabies infection History or evidence of any other acute or chronic disease that, in the opinion of the investigator, may interfere with the evaluation of the safety or immunogenicity of the drug or compromise the safety of the subject; for example a clinically relevant history of respiratory, thyroid, gastrointestinal, renal, hepatic, hematological, lymphatic, oncologic, cardiovascular, psychiatric, neurological, musculoskeletal, genitourinary, infective, inflammatory, immunological, dermatological or connective tissue disease History or evidence of allergic disease or reaction, including adverse responses to therapeutic monoclonal antibodies that, in the opinion of the investigator, may compromise the safety of the subject History of non-compliance that, in the opinion of the investigator, will make it unlikely that the subject will comply with the protocol Previous exposure to rabies vaccine Receipt of an immunoglobulin or blood product within 90 days prior to Study Day 0 Receipt of immunosuppressive medications other than inhaled or topical immunosuppressant drugs within 45 days prior to Study Day 0 Body weight greater than 90 kg. History or evidence of IgA deficiency

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Imovax, SYN023<br>Subjects will receive SYN023 and 5 doses of Imovax rabies vaccine | Biological: SYN023<br>* The effects of SYN023 on immunogenicity of rabies vaccines Imovax and RabAvert will be compared to the effect of human rabies immune globulin.<br>Biological: Imovax<br>* Subjects will receive SYN023 or HyperRAB ST (human rabies immune globulin) and 5 doses of Imovax rabies vaccine<br>|
| Active Comparator: Imovax, human rabies immune globulin<br>Subjects will receive HyperRAB ST (human rabies immune globulin) and 5 doses of Imovax rabies vaccine | Biological: Imovax<br>* Subjects will receive SYN023 or HyperRAB ST (human rabies immune globulin) and 5 doses of Imovax rabies vaccine<br>Biological: HyperRAB ST (human rabies immune globulin)<br>* The effects of SYN023 on immunogenicity of rabies vaccines Imovax and RabAvert will be compared to the effect of human rabies immune globulin.<br>|
| Experimental: RabAvert, SYN023<br>Subjects will receive SYN023 and 5 doses of RabAvert rabies vaccine | Biological: SYN023<br>* The effects of SYN023 on immunogenicity of rabies vaccines Imovax and RabAvert will be compared to the effect of human rabies immune globulin.<br>Biological: RabAvert<br>* Subjects will receive SYN023 or HyperRAB ST (human rabies immune globulin) and 5 doses of RabAvert rabies vaccine<br>|
| Active Comparator: RabAvert, human rabies immune globulin<br>Subjects will receive HyperRAB ST (human rabies immune globulin) and 5 doses of RabAvert rabies vaccine | Biological: RabAvert<br>* Subjects will receive SYN023 or HyperRAB ST (human rabies immune globulin) and 5 doses of RabAvert rabies vaccine<br>Biological: HyperRAB ST (human rabies immune globulin)<br>* The effects of SYN023 on immunogenicity of rabies vaccines Imovax and RabAvert will be compared to the effect of human rabies immune globulin.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Serum Rabies Virus Neutralizing Activity | Inhibitory activity of serum in standard rabies virus inhibition test (RFFIT: Rapid Fluorescent Foci Inhibition Test) assessed as serum RVNA ≥ 0.5 IU/mL. RFFIT is a serum neutralization (inhibition) test, which means it measures the ability of rabies specific antibodies to neutralize rabies virus and prevent the virus from infecting cells. These antibodies are called rabies virus neutralizing antibodies (RVNA). | 112 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Adverse Event Incidence of SYN023 Compared to HRIG in RabAvert and Imovax Reciptients | Electrocardiograms are performed to monitor subject safety. Laboratory evaluations for subject safety (adverse events) are serum chemistry evaluations, blood urea nitrogen, creatinine, bilirubin, alanine amino transferase, aspartate amino transferase, creatine phosphokinase, troponin, potassium, sodium, bicarbonate, calcium, complete blood count, platelet count, differential count, PT(prothrombin time, international normalized ratio) and PTT (partial prothrombin time and urinalyses for monitoring of safety. Additional laboratory tests may be required for evaluation of specific adverse events such as anaphylaxis and immune complex diseases. Adverse events and serious adverse events will be analyzed. A comparison of adverse event incidence between the four treatment groups will be performed. | 42 days | 
| Percentage of Participants With Immunogenicity: Anti-CTB012 Antibodies Positive | Measurement of the development of anti-CTB012 antibodies (a component of anti-SYN023 antibodies) in participants which will be analyzed on a continuous scale as a categorical variable by treatment assignment, with descriptive statistics. | 112 days | 
| Percentage of Participants With Immunogenicity: Anti-CTB011 Antibodies Positive | Measurement of the development of anti-CTB011 antibodies (a component of anti-SYN023 antibodies) in participants which will be analyzed on a continuous scale as a categorical variable by treatment assignment, with descriptive statistics. | 112 days | 
| SYN023 Monoclonal Antibody Areas Under the Curve (AUC0-last, AUC0-inf) for CTB011 and CTB012) | The area under the time concentration curve for SYN023 mAb components CTB011 and CTB012 will be estimated at Day 0 ( pre-dose), Day 1, Day 3, Day 7, Day 14, Day 28, Day 35, Day 42, and Day 84 post-dose, using non compartmental analysis. | 84 days | 
| Time to Maximum Concentration Tmax of CTB011 and CTB012 | Interval from time 0 to maximum measured concentration of CTB011 and CTB012 (SYN023 components) at Day 0 ( pre-dose), Day 1, Day 3, Day 7, Day 14, Day 28, Day 35, Day 42, and Day 84 post-dose, using non compartmental analysis. | 84 days | 
| Maximum Serum Concentration Cmax | Maximum concentration of of CTB011 and CTB012 at Day 0 ( pre-dose), Day 1, Day 3, Day 7, Day 14, Day 28, Day 35, Day 42, and Day 84 post-dose, using non compartmental analysis. | 84 days | 
| Serum Clearance Rate (Clp) of CTB011 and CTB012 | Calculated serum clearance rates for CTB011 and CTB012 at Day 0 ( pre-dose), Day 1, Day 3, Day 7, Day 14, Day 28, Day 35, Day 42, and Day 84 post-dose, using non compartmental analysis. | 84 days | 
| Serum Half Lives of CTB011 and CTB012 | The time in hours to reduce the serum concnetration of CTB011 and CTB012 to 50% of the maximum serum concentration at Day 0 ( pre-dose), Day 1, Day 3, Day 7, Day 14, Day 28, Day 35, Day 42, and Day 84 post-dose, using non compartmental analysis. | 84 days |