Healthy
Conditions
Brief summary
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
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.
Interventions
Sponsors
Bio Products Laboratory
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
Double-blind study
Intervention model description
Treatment A: BPL HRIG + active rabies vaccine Treatment B: Comparator HRIG + active rabies vaccine
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
1. Able and willing to sign an informed consent form. 2. Healthy male or female subjects aged 18 - 75 years inclusive. 3. No previous exposure to rabies virus, rabies vaccine and/or rabies immunoglobulin. 4. No significant abnormalities in hematology, biochemistry, or urinalysis according to the Principal Investigator's judgment. 5. No significant abnormalities in ECG according to the Investigator's judgment. 6. 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. 7. 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
1. Female subjects who are pregnant and/or lactating. 2. History of live virus vaccination, e.g., measles, mumps, varicella or rubella vaccine, within the last 3 months. 3. Planned live virus vaccination, e.g., measles, mumps, varicella or rubella vaccine, within the 3 months after Day 0. 4. 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 5. 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. 6. History of life-threatening allergy, anaphylactic reaction, or systemic response to human plasma derived products. 7. History of life-threatening allergy to blood or blood products. 8. 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. 9. History of or ongoing bleeding disorder. 10. Previous organ transplant recipient. 11. Ongoing immunosuppressive illness. 12. 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. 13. 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. 14. Evidence of active systemic infection that requires treatment with antibiotics within 2 weeks prior to Day 0. 15. Currently receiving or have received within the past 6 months (prior to Day 0): * immunosuppressive drugs * immunomodulatory drugs 16. 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. 17. Evidence of uncontrolled hypertension (systolic blood pressure of \>150 mmHg, and/or diastolic blood pressure of \>100 mmHg). 18. Heart rate \>120/min. 19. Weight \> 95.5 kg 20. History of IgA deficiency. 21. Is positive for any of the following at screening: serological test for HIV 1&2, HCV or HBsAg. 22. 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. 23. Previous enrollment in this study. 24. Participation in an interventional clinical trial within 30 days prior to baseline visit (Day 0). 25. Evidence of alcohol abuse or history of alcohol abuse or illegal and/or legally prescribed drugs in the past 2 years. 26. Any other factor that, in the opinion of the investigator, would prevent the subject from complying with the requirements of the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Subjects With Anti-rabies Antibody Titer of ≥0.5 IU/mL | Day 14 | 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%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Analysis of AUC0-7d | Day 0 to Day 7 | The AUC0-7d for BPL HRIG and vaccine versus comparator HRIG and vaccine using a non inferiority margin of 20%. |
| RVNA Geometric Mean Titers at Days 3, 5, 7 and 14 | 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. |
| Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ 0.5 IU/mL by Visit | Days 3, 5, 7, 14, 28, 49, and 140 | 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. |
| Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ LLOQ of the Assay by Visit | Days 3, 5, 7, 14, 28, 49, and 140 | 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. |
| RVNA Geometric Mean Titers at Days 14, 28, 49 and 140 | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| BPL HRIG + RabAvert 20 IU/kg dose HRIG + active rabies vaccine
HRIG: A 20 IU/kg dose of BPL HRIG will be given on Day 0 via IM injection.
RabAvert: 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. | 81 |
| Comparator HyperRab + RabAvert 20 IU/kg dose HRIG + active rabies vaccine
HyperRAB: A 20 IU/kg dose of Comparator HRIG will be given on Day 0 via IM injection.
RabAvert: 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. | 81 |
| Total | 162 |
Baseline characteristics
| Characteristic | Total | BPL HRIG + RabAvert | Comparator HyperRab + RabAvert |
|---|---|---|---|
| Age, Continuous | 42.96 years STANDARD_DEVIATION 15.2 | 41.37 years STANDARD_DEVIATION 15 | 44.56 years STANDARD_DEVIATION 15.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 5 Participants | 2 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 157 Participants | 79 Participants | 78 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 31 Participants | 16 Participants | 15 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 121 Participants | 62 Participants | 59 Participants |
| Region of Enrollment United States | 162 participants | 81 participants | 81 participants |
| Sex: Female, Male Female | 110 Participants | 56 Participants | 54 Participants |
| Sex: Female, Male Male | 52 Participants | 25 Participants | 27 Participants |
| Weight | 74.56 kg STANDARD_DEVIATION 12.8 | 74.61 kg STANDARD_DEVIATION 12.5 | 74.51 kg STANDARD_DEVIATION 13.2 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 81 | 0 / 81 |
| other Total, other adverse events | 19 / 81 | 19 / 81 |
| serious Total, serious adverse events | 0 / 81 | 0 / 81 |
Outcome results
Primary
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%.
Time frame: Day 14
Population: Primary PK population (all subjects who receive the full dose of BPL HRIG or comparator HRIG and the first 3 doses of active rabies vaccine on Days 0, 3, 7 and for whom the PK sample at Day 14 is taken).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| BPL HRIG + RabAvert | Proportion of Subjects With Anti-rabies Antibody Titer of ≥0.5 IU/mL | 73 Participants |
| Comparator HyperRab + RabAvert | Proportion of Subjects With Anti-rabies Antibody Titer of ≥0.5 IU/mL | 72 Participants |
p-value: 0.0006Farrington and Manning test
Secondary
Analysis of AUC0-7d
The AUC0-7d for BPL HRIG and vaccine versus comparator HRIG and vaccine using a non inferiority margin of 20%.
Time frame: Day 0 to Day 7
Population: Primary PK population (all subjects who receive the full dose of BPL HRIG or comparator HRIG and the first 3 doses of active rabies vaccine on Days 0, 3, 7 and for whom the PK sample at Day 14 is taken).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| BPL HRIG + RabAvert | Analysis of AUC0-7d | 1.10 day*IU/mL |
| Comparator HyperRab + RabAvert | Analysis of AUC0-7d | 1.32 day*IU/mL |
95% CI: [0.74, 0.94]
Secondary
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.
Time frame: Days 3, 5, 7, 14, 28, 49, and 140
Population: Primary PK population (all subjects who receive the full dose of BPL HRIG or comparator HRIG and the first 3 doses of active rabies vaccine on Days 0, 3, 7 and for whom the PK sample at Day 14 is taken).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BPL HRIG + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ 0.5 IU/mL by Visit | Day 14 | 73 Participants |
| BPL HRIG + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ 0.5 IU/mL by Visit | Day 3 | 0 Participants |
| BPL HRIG + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ 0.5 IU/mL by Visit | Day 28 | 73 Participants |
| BPL HRIG + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ 0.5 IU/mL by Visit | Day 0 | 0 Participants |
| BPL HRIG + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ 0.5 IU/mL by Visit | Day 49 | 73 Participants |
| BPL HRIG + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ 0.5 IU/mL by Visit | Day 5 | 0 Participants |
| BPL HRIG + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ 0.5 IU/mL by Visit | Day 140 | 60 Participants |
| BPL HRIG + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ 0.5 IU/mL by Visit | Day 7 | 3 Participants |
| Comparator HyperRab + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ 0.5 IU/mL by Visit | Day 140 | 65 Participants |
| Comparator HyperRab + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ 0.5 IU/mL by Visit | Day 7 | 2 Participants |
| Comparator HyperRab + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ 0.5 IU/mL by Visit | Day 0 | 0 Participants |
| Comparator HyperRab + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ 0.5 IU/mL by Visit | Day 3 | 1 Participants |
| Comparator HyperRab + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ 0.5 IU/mL by Visit | Day 5 | 1 Participants |
| Comparator HyperRab + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ 0.5 IU/mL by Visit | Day 14 | 72 Participants |
| Comparator HyperRab + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ 0.5 IU/mL by Visit | Day 28 | 73 Participants |
| Comparator HyperRab + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ 0.5 IU/mL by Visit | Day 49 | 72 Participants |
p-value: 0.000695% CI: [-0.05, 0.1]Farrington and Manning test
Secondary
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.
Time frame: Days 3, 5, 7, 14, 28, 49, and 140
Population: Primary PK population (all subjects who receive the full dose of BPL HRIG or comparator HRIG and the first 3 doses of active rabies vaccine on Days 0, 3, 7 and for whom the PK sample at Day 14 is taken).
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| BPL HRIG + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ LLOQ of the Assay by Visit | Day 5 | 71 Participants |
| BPL HRIG + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ LLOQ of the Assay by Visit | Day 7 | 73 Participants |
| BPL HRIG + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ LLOQ of the Assay by Visit | Day 0 | 0 Participants |
| BPL HRIG + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ LLOQ of the Assay by Visit | Day 3 | 70 Participants |
| BPL HRIG + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ LLOQ of the Assay by Visit | Day 14 | 73 Participants |
| BPL HRIG + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ LLOQ of the Assay by Visit | Day 28 | 73 Participants |
| BPL HRIG + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ LLOQ of the Assay by Visit | Day 49 | 73 Participants |
| BPL HRIG + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ LLOQ of the Assay by Visit | Day 140 | 62 Participants |
| Comparator HyperRab + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ LLOQ of the Assay by Visit | Day 140 | 71 Participants |
| Comparator HyperRab + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ LLOQ of the Assay by Visit | Day 5 | 74 Participants |
| Comparator HyperRab + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ LLOQ of the Assay by Visit | Day 14 | 74 Participants |
| Comparator HyperRab + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ LLOQ of the Assay by Visit | Day 49 | 72 Participants |
| Comparator HyperRab + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ LLOQ of the Assay by Visit | Day 0 | 0 Participants |
| Comparator HyperRab + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ LLOQ of the Assay by Visit | Day 28 | 74 Participants |
| Comparator HyperRab + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ LLOQ of the Assay by Visit | Day 3 | 73 Participants |
| Comparator HyperRab + RabAvert | Proportion of Subjects Reaching Antirabies Antibody Titer of ≥ LLOQ of the Assay by Visit | Day 7 | 74 Participants |
p-value: 095% CI: [0, 0]Farrington and Manning test
Secondary
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.
Time frame: Days 14, 28, 49 and 140
Population: Secondary PK population (subjects who receive the full dose of BPL HRIG or comparator HRIG and all 5 doses of active rabies vaccine and for whom all required PK samples are taken).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| BPL HRIG + RabAvert | RVNA Geometric Mean Titers at Days 14, 28, 49 and 140 | Day 14 | 12.30 IU/mL |
| BPL HRIG + RabAvert | RVNA Geometric Mean Titers at Days 14, 28, 49 and 140 | Day 28 | 10.18 IU/mL |
| BPL HRIG + RabAvert | RVNA Geometric Mean Titers at Days 14, 28, 49 and 140 | Day 49 | 10.91 IU/mL |
| BPL HRIG + RabAvert | RVNA Geometric Mean Titers at Days 14, 28, 49 and 140 | Day 140 | 2.72 IU/mL |
| Comparator HyperRab + RabAvert | RVNA Geometric Mean Titers at Days 14, 28, 49 and 140 | Day 140 | 2.02 IU/mL |
| Comparator HyperRab + RabAvert | RVNA Geometric Mean Titers at Days 14, 28, 49 and 140 | Day 14 | 8.38 IU/mL |
| Comparator HyperRab + RabAvert | RVNA Geometric Mean Titers at Days 14, 28, 49 and 140 | Day 49 | 7.78 IU/mL |
| Comparator HyperRab + RabAvert | RVNA Geometric Mean Titers at Days 14, 28, 49 and 140 | Day 28 | 7.78 IU/mL |
Secondary
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.
Time frame: Days 3, 5, 7 and 14
Population: Secondary PK population (subjects who receive the full dose of BPL HRIG or comparator HRIG and all 5 doses of active rabies vaccine and for whom all required PK samples are taken).
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| BPL HRIG + RabAvert | RVNA Geometric Mean Titers at Days 3, 5, 7 and 14 | Day 3 | 0.18 IU/mL |
| BPL HRIG + RabAvert | RVNA Geometric Mean Titers at Days 3, 5, 7 and 14 | Day 7 | 0.23 IU/mL |
| BPL HRIG + RabAvert | RVNA Geometric Mean Titers at Days 3, 5, 7 and 14 | Through Day 14 | 0.37 IU/mL |
| BPL HRIG + RabAvert | RVNA Geometric Mean Titers at Days 3, 5, 7 and 14 | Day 14 | 12.30 IU/mL |
| BPL HRIG + RabAvert | RVNA Geometric Mean Titers at Days 3, 5, 7 and 14 | Day 5 | 0.19 IU/mL |
| Comparator HyperRab + RabAvert | RVNA Geometric Mean Titers at Days 3, 5, 7 and 14 | Day 14 | 8.38 IU/mL |
| Comparator HyperRab + RabAvert | RVNA Geometric Mean Titers at Days 3, 5, 7 and 14 | Through Day 14 | 0.38 IU/mL |
| Comparator HyperRab + RabAvert | RVNA Geometric Mean Titers at Days 3, 5, 7 and 14 | Day 3 | 0.21 IU/mL |
| Comparator HyperRab + RabAvert | RVNA Geometric Mean Titers at Days 3, 5, 7 and 14 | Day 5 | 0.24 IU/mL |
| Comparator HyperRab + RabAvert | RVNA Geometric Mean Titers at Days 3, 5, 7 and 14 | Day 7 | 0.26 IU/mL |