Safety and Effectiveness of BPL HRIG With Active Rabies Vaccine in Healthy Subjects

Study Overview
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Brief Summary
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A prospective, randomized, blinded, parallel-group, non-inferiority, phase II/III study of the safety and effectiveness of simulated post-exposure prophylaxis with BPL HRIG with co-administration of active rabies vaccine in healthy subjects.

Detailed Description
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Each subject will undergo a total of 9 visits. Subjects' eligibility will be assessed at Screening, which can occur up to 28 days prior to dosing. Following a repeat eligibility check at Day 0, eligible subjects will be randomized and dosed with the randomized treatment (BPL HRIG + vaccine or Comparator HRIG + vaccine) on Day 0. Further assessments will be conducted on Days 3, 5, 7, 14, 28, 49 and the end of study assessment on Day 140. Vaccine will be administered on Day 0, 3, 7, 14 and 28.

Official Title
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A Prospective, Randomized, Double-Blind Parallel-group, Non-inferiority Phase II/III Study of the Safety and Effectiveness of BPL HRIG With Co Administration of Active Rabies Vaccine in Healthy Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: HRIG
* Drug: HyperRAB
* Biological: RabAvert


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to sign an informed consent form. Healthy male or female subjects aged 18 - 75 years inclusive. No previous exposure to rabies virus, rabies vaccine and/or rabies immunoglobulin. No significant abnormalities in hematology, biochemistry, or urinalysis according to the Principal Investigator's judgment. No significant abnormalities in ECG according to the Investigator's judgment. Females of child-bearing potential (defined from the onset of menstruation to one-year post- menopause and not surgically sterilized) who are (or become) sexually active must agree to practice contraception by using a highly effective (>98%) method for the duration of the study. Females of child-bearing potential (defined from the onset of menstruation to one-year post- menopause and not surgically sterilized) must have a negative result on a serum at screening visit and a urine HCG-based pregnancy test at Day 0. Exclusion Criteria Female subjects who are pregnant and/or lactating. History of live virus vaccination, e.g., measles, mumps, varicella or rubella vaccine, within the last 3 months. Planned live virus vaccination, e.g., measles, mumps, varicella or rubella vaccine, within the 3 months after Day 0. History of anaphylactic or anaphylactoid hypersensitivity reactions to chicken egg; history of mild allergic reactions to chicken egg, e.g., skin rash only, is not an exclusion criterion History of hypersensitivity reaction to any of the following components of active rabies vaccine (US-FDA approved) e.g.: neomycin, bovine gelatin, trace amounts of chicken protein, chlortetracycline, and amphotericin B and in accordance with the product insert of the vaccine. History of life-threatening allergy, anaphylactic reaction, or systemic response to human plasma derived products. History of life-threatening allergy to blood or blood products. Fever at the time of the start of the injection (oral temperature >38ºC.) or acute illness at the time of the start of the injection. Subjects with fever on Day 0 may have entry to the study re-scheduled. History of or ongoing bleeding disorder. Previous organ transplant recipient. Ongoing immunosuppressive illness. Clinically significant illnesses including: cardiac, hepatic, renal, endocrine, neurological, hematological, neoplastic, immunological, skeletal or other) that in the opinion of the investigator, could interfere with the safety, compliance or other aspects of this study. All types of malignancies except for basal and squamous cell (scaly or plate-like) skin cancer, in- situ cervical carcinoma must be in remission for a minimum of 5 years prior to Day 0. For non-melanoma skin cancers and carcinoma in-situ of the cervix may be enrolled if treated and cured at the time of screening. Evidence of active systemic infection that requires treatment with antibiotics within 2 weeks prior to Day 0. Currently receiving or have received within the past 6 months (prior to Day 0): immunosuppressive drugs immunomodulatory drugs Currently receiving or have received oral or IV steroids within 14 days (prior to DAY 0) or expected to require oral or IV steroids during the study. Evidence of uncontrolled hypertension (systolic blood pressure of >150 mmHg, and/or diastolic blood pressure of >100 mmHg). Heart rate >120/min. Weight > 95.5 kg History of IgA deficiency. Is positive for any of the following at screening: serological test for HIV 1&2, HCV or HBsAg. Presence of psychiatric disorder, other mental disorder or any other medical disorder which might impair the subject's ability to give informed consent or to comply with the requirements of the study protocol. Previous enrollment in this study. Participation in an interventional clinical trial within 30 days prior to baseline visit (Day 0). Evidence of alcohol abuse or history of alcohol abuse or illegal and/or legally prescribed drugs in the past 2 years. Any other factor that, in the opinion of the investigator, would prevent the subject from complying with the requirements of the protocol.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Treatment A: BPL HRIG + active rabies vaccine Treatment B: Comparator HRIG + active rabies vaccine
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BPL HRIG + RabAvert<br>20 IU/kg dose HRIG + active rabies vaccine | Drug: HRIG<br>* A 20 IU/kg dose of BPL HRIG will be given on Day 0 via IM injection.<br>Biological: RabAvert<br>* A 1.0 ml dose of active vaccine (2.5 IU/ml) will be given IM on 5 occasions: on Days 0, 3, 7, 14, and 28.<br>* Other names: active rabies vaccine;|
| Active Comparator: Comparator HyperRab + RabAvert<br>20 IU/kg dose HRIG + active rabies vaccine | Drug: HyperRAB<br>* A 20 IU/kg dose of Comparator HRIG will be given on Day 0 via IM injection.<br>* Other names: HRIG;Biological: RabAvert<br>* A 1.0 ml dose of active vaccine (2.5 IU/ml) will be given IM on 5 occasions: on Days 0, 3, 7, 14, and 28.<br>* Other names: active rabies vaccine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Subjects With Anti-rabies Antibody Titer of ≥0.5 IU/mL | Non-inferiority in terms of the proportion of subjects with anti-rabies antibody titer of ≥0.5 IU/mL after study drug administration using a non-inferiority margin of 10%. | Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Analysis of AUC0-7d | The AUC0-7d for BPL HRIG and vaccine versus comparator HRIG and vaccine using a non inferiority margin of 20%. | Day 0 to Day 7 | 
| RVNA Geometric Mean Titers at Days 3, 5, 7 and 14 | Comparison of the geometric mean titers (GMTs) for antirabies antibody titer after administration of BPL HRIG and vaccine versus comparator HRIG and vaccine. The median peak RVNA titer occurred at Day 14, which is reflected in the analysis. The RVNA titer to peak geometric mean is analyzed using a repeated measures analysis. The inferential test compares RVNA values between BPL HRIG and HyperRab in a single analysis across all visits at or below the visit at which peak titer is observed. The geometric mean values presented represent a mean across all visits from baseline through and including Day 14. | Days 3, 5, 7 and 14 | 
| Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ 0.5 IU/mL by Visit | The proportion of subjects reaching antirabies antibody titer of ≥ 0.5 IU/mL after administration of BPL HRIG and vaccine versus comparator HRIG and vaccine. | Days 3, 5, 7, 14, 28, 49, and 140 | 
| Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ LLOQ of the Assay by Visit | The proportion of subjects reaching antirabies antibody titer of ≥ LLOQ of the assay at each visit after administration of BPL HRIG and vaccine versus comparator HRIG and vaccine. | Days 3, 5, 7, 14, 28, 49, and 140 | 
| RVNA Geometric Mean Titers at Days 14, 28, 49 and 140 | Comparison of the GMTs for antirabies antibody titer after administration of BPL HRIG and vaccine versus comparator HRIG and vaccine to assess the inhibitory effects of BPL HRIG on active immunization relative to that of the comparator HRIG. | Days 14, 28, 49 and 140 |