Rabies
Conditions
Keywords
Rabies, rabies vaccines, post-exposure prophylaxis
Brief summary
This study was planned to establish the non-inferiority of Rabipur administered as simulated post exposure Zagreb schedule as compared to Essen schedule, in healthy Indian adult subjects.
Interventions
BIOLOGICALPurified Chick Embryo Cell Inactivated Rabies Vaccine
Two group (Zagreb and Essen) will receive Rabipur vaccine IM according to either Zagreb or Essen schedules.
Sponsors
Novartis Vaccines
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
1. Males and females of age ≥ 18 years. 2. Individuals who had given written consent. 3. Individuals in good health and available for all the visits scheduled in the study.
Exclusion criteria
1. Pregnancy or unwillingness to practice acceptable contraception. 2. A history of Rabies vaccination. 3. History of allergy to egg protein. 4. Known hypersensitivity to neomycin, tetracycline, amphotericin-B or any other vaccine component. 5. A significant acute or chronic infectious disease or use of antibiotics that may impact the subject's safety and /or immunogenicity in the Investigators opinion at the time of enrolment. 6. Body temperature ≥38.0°C (≥ 100.4°F) within 3 days of study vaccination. 7. Treatment with an anti-malarial drug, up to two months prior to the study. 8. Individuals who received any other vaccines within 28 days prior to enrollment. 9. Subjects who have received blood, blood products and/or plasma derivatives or any parenteral immunoglobulin preparation in the past 12 weeks. 10. Any planned surgery during the study period. 11. Subjects who have cancer disorders excluding nonmelanotic skin cancer.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Geometric Mean Rabies Virus Neutralizing Antibody (RVNA) Concentration in Each of the Zagreb and Essen Groups on Study Day 14 | On Day 0 and Day 14 | Immunogenicity was measured as the geometric mean concentrations (GMCs) of rabies virus neutralizing antibody (RVNA) titer , evaluated using the rapid fluorescent focus inhibition test, before vaccination and on study day 14 as per Zagreb (2-1-1) and Essen (1-1-1-1-1) postexposure schedule |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentages of Subjects With Anti-RVNA Titer ≥0.5 IU/mL in Zagreb and Essen Groups at Days 7, 14 and 42 | Study day 7, 14 and 42 | Immunogenicity was measured as the percentage of subjects who achieved anti-RVNA titer ≥0.5 IU/mL, at days 0, 7, 14 and 42 as per Zagreb (2-1-1) and Essen (1-1-1-1-1) postexposure schedule. |
| Ratio of GMCs in Study Groups (Zagreb/Essen Schedules) on Days 7 and 42 as Measured by RVNA Geometric Mean Concentrations | Day 0, Day 7, Day 14 and Day 42 | Immunogenicity was measured as the ratio of GMCs of RVNA titer , evaluated using the rapid fluorescent focus inhibition test, on Days 7 and 42 as per Zagreb (2-1-1) and Essen (1-1-1-1-1) postexposure schedules |
| Percentages of Subjects Reporting Adverse Events (AEs) | All reported SAEs and medically attended AEs or AEs that resulted in the premature withdrawal of subjects were collected up to 42 days after first vaccination. Adverse events were collected throughout the study period | Adverse events (AEs) were collected for 7 days following administration of each study vaccination or until time of next vaccination (whichever occurred sooner). All reported SAEs and medically attended AEs or AEs that resulted in the premature withdrawal of subjects during the study were collected throughout the study period and all AEs were unsolicited. |
Countries
India
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Zagreb Rabipur vaccine, administered intramuscularly (IM) according to the 2-1-1 (Zagreb) schedule (i.e., 2 doses of vaccine administered on day 0 and 1 dose of vaccine each administered on day 7 and day 21)
Purified Chick Embryo Cell Inactivated Rabies Vaccine: Zagreb group received Rabipur vaccine intramuscularly according to Zagreb schedules. | 126 |
| Essen Rabipur vaccine, administered IM according to the 1-1-1-1-1 (Essen) schedule (i.e., 1 dose of vaccine administered on day 0, 3, 7, 14 and 28)
Purified Chick Embryo Cell Inactivated Rabies Vaccine: Essen group received Rabipur vaccine intramuscularly according to Essen schedules. | 124 |
| Total | 250 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Lost to Follow-up | 1 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Zagreb | Essen | Total |
|---|---|---|---|
| Age, Continuous | 29.1 years STANDARD_DEVIATION 8.8 | 27.2 years STANDARD_DEVIATION 7.3 | 28.2 years STANDARD_DEVIATION 8.1 |
| Sex: Female, Male Female | 54 Participants | 58 Participants | 112 Participants |
| Sex: Female, Male Male | 72 Participants | 66 Participants | 138 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 126 | 8 / 123 |
| serious Total, serious adverse events | 0 / 126 | 0 / 123 |
Outcome results
Primary
Geometric Mean Rabies Virus Neutralizing Antibody (RVNA) Concentration in Each of the Zagreb and Essen Groups on Study Day 14
Immunogenicity was measured as the geometric mean concentrations (GMCs) of rabies virus neutralizing antibody (RVNA) titer , evaluated using the rapid fluorescent focus inhibition test, before vaccination and on study day 14 as per Zagreb (2-1-1) and Essen (1-1-1-1-1) postexposure schedule
Time frame: On Day 0 and Day 14
Population: Per Protocol Set-All subjects in the FAS (Full analysis set) population who:correctly receive the vaccine, provide evaluable serum sample at day 14, and have no major protocol violation as defined prior to analysis
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Zagreb | Geometric Mean Rabies Virus Neutralizing Antibody (RVNA) Concentration in Each of the Zagreb and Essen Groups on Study Day 14 | Day 0 | 0.09 IU/mL |
| Zagreb | Geometric Mean Rabies Virus Neutralizing Antibody (RVNA) Concentration in Each of the Zagreb and Essen Groups on Study Day 14 | Day 14 | 12 IU/mL |
| Essen | Geometric Mean Rabies Virus Neutralizing Antibody (RVNA) Concentration in Each of the Zagreb and Essen Groups on Study Day 14 | Day 0 | 0.099 IU/mL |
| Essen | Geometric Mean Rabies Virus Neutralizing Antibody (RVNA) Concentration in Each of the Zagreb and Essen Groups on Study Day 14 | Day 14 | 12 IU/mL |
Comparison: To demonstrate non-inferiority in immune response of the Zagreb postexposure schedule of Rabipur to that of the conventional Essen postexposure schedule at study day 1495% CI: [0.89, 1.19]ANOVA
Secondary
Percentages of Subjects Reporting Adverse Events (AEs)
Adverse events (AEs) were collected for 7 days following administration of each study vaccination or until time of next vaccination (whichever occurred sooner). All reported SAEs and medically attended AEs or AEs that resulted in the premature withdrawal of subjects during the study were collected throughout the study period and all AEs were unsolicited.
Time frame: All reported SAEs and medically attended AEs or AEs that resulted in the premature withdrawal of subjects were collected up to 42 days after first vaccination. Adverse events were collected throughout the study period
Population: Safety population- All subjects in the Exposed population who provide post vaccination safety data and as vaccinated (as treated)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zagreb | Percentages of Subjects Reporting Adverse Events (AEs) | SAE | 0 percentages of subjects |
| Zagreb | Percentages of Subjects Reporting Adverse Events (AEs) | Deaths | 0 percentages of subjects |
| Zagreb | Percentages of Subjects Reporting Adverse Events (AEs) | At least possibly related AEs | 4 percentages of subjects |
| Zagreb | Percentages of Subjects Reporting Adverse Events (AEs) | Medically Attended AEs | 0 percentages of subjects |
| Zagreb | Percentages of Subjects Reporting Adverse Events (AEs) | At least possibly related SAEs | 0 percentages of subjects |
| Zagreb | Percentages of Subjects Reporting Adverse Events (AEs) | Withdrawal from study due to AE | 0.8 percentages of subjects |
| Zagreb | Percentages of Subjects Reporting Adverse Events (AEs) | Any AEs | 17 percentages of subjects |
| Essen | Percentages of Subjects Reporting Adverse Events (AEs) | Withdrawal from study due to AE | 0 percentages of subjects |
| Essen | Percentages of Subjects Reporting Adverse Events (AEs) | Any AEs | 15 percentages of subjects |
| Essen | Percentages of Subjects Reporting Adverse Events (AEs) | At least possibly related AEs | 11 percentages of subjects |
| Essen | Percentages of Subjects Reporting Adverse Events (AEs) | SAE | 0 percentages of subjects |
| Essen | Percentages of Subjects Reporting Adverse Events (AEs) | At least possibly related SAEs | 0 percentages of subjects |
| Essen | Percentages of Subjects Reporting Adverse Events (AEs) | Deaths | 0 percentages of subjects |
| Essen | Percentages of Subjects Reporting Adverse Events (AEs) | Medically Attended AEs | 0 percentages of subjects |
Secondary
Percentages of Subjects With Anti-RVNA Titer ≥0.5 IU/mL in Zagreb and Essen Groups at Days 7, 14 and 42
Immunogenicity was measured as the percentage of subjects who achieved anti-RVNA titer ≥0.5 IU/mL, at days 0, 7, 14 and 42 as per Zagreb (2-1-1) and Essen (1-1-1-1-1) postexposure schedule.
Time frame: Study day 7, 14 and 42
Population: Full Analysis Set- All subjects in the exposed population who provided at least one evaluable serum sample and as randomized
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zagreb | Percentages of Subjects With Anti-RVNA Titer ≥0.5 IU/mL in Zagreb and Essen Groups at Days 7, 14 and 42 | Day 0 | 6 Percentages of Subjects |
| Zagreb | Percentages of Subjects With Anti-RVNA Titer ≥0.5 IU/mL in Zagreb and Essen Groups at Days 7, 14 and 42 | Day 7(N=125,123) | 74 Percentages of Subjects |
| Zagreb | Percentages of Subjects With Anti-RVNA Titer ≥0.5 IU/mL in Zagreb and Essen Groups at Days 7, 14 and 42 | Day 14(N=124,123) | 100 Percentages of Subjects |
| Zagreb | Percentages of Subjects With Anti-RVNA Titer ≥0.5 IU/mL in Zagreb and Essen Groups at Days 7, 14 and 42 | Day 42(N=124,121) | 100 Percentages of Subjects |
| Essen | Percentages of Subjects With Anti-RVNA Titer ≥0.5 IU/mL in Zagreb and Essen Groups at Days 7, 14 and 42 | Day 42(N=124,121) | 100 Percentages of Subjects |
| Essen | Percentages of Subjects With Anti-RVNA Titer ≥0.5 IU/mL in Zagreb and Essen Groups at Days 7, 14 and 42 | Day 0 | 9 Percentages of Subjects |
| Essen | Percentages of Subjects With Anti-RVNA Titer ≥0.5 IU/mL in Zagreb and Essen Groups at Days 7, 14 and 42 | Day 14(N=124,123) | 100 Percentages of Subjects |
| Essen | Percentages of Subjects With Anti-RVNA Titer ≥0.5 IU/mL in Zagreb and Essen Groups at Days 7, 14 and 42 | Day 7(N=125,123) | 97 Percentages of Subjects |
Secondary
Ratio of GMCs in Study Groups (Zagreb/Essen Schedules) on Days 7 and 42 as Measured by RVNA Geometric Mean Concentrations
Immunogenicity was measured as the ratio of GMCs of RVNA titer , evaluated using the rapid fluorescent focus inhibition test, on Days 7 and 42 as per Zagreb (2-1-1) and Essen (1-1-1-1-1) postexposure schedules
Time frame: Day 0, Day 7, Day 14 and Day 42
Population: Full Analysis Set- All subjects in the exposed population who provided at least one evaluable serum sample and as randomized
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Zagreb | Ratio of GMCs in Study Groups (Zagreb/Essen Schedules) on Days 7 and 42 as Measured by RVNA Geometric Mean Concentrations | Day 0 | 0.091 IU\ml |
| Zagreb | Ratio of GMCs in Study Groups (Zagreb/Essen Schedules) on Days 7 and 42 as Measured by RVNA Geometric Mean Concentrations | Day 7(N=125,123) | 0.66 IU\ml |
| Zagreb | Ratio of GMCs in Study Groups (Zagreb/Essen Schedules) on Days 7 and 42 as Measured by RVNA Geometric Mean Concentrations | Day 14(N=124,123) | 12 IU\ml |
| Zagreb | Ratio of GMCs in Study Groups (Zagreb/Essen Schedules) on Days 7 and 42 as Measured by RVNA Geometric Mean Concentrations | Day 42(N=124,121) | 15 IU\ml |
| Essen | Ratio of GMCs in Study Groups (Zagreb/Essen Schedules) on Days 7 and 42 as Measured by RVNA Geometric Mean Concentrations | Day 42(N=124,121) | 16 IU\ml |
| Essen | Ratio of GMCs in Study Groups (Zagreb/Essen Schedules) on Days 7 and 42 as Measured by RVNA Geometric Mean Concentrations | Day 0 | 0.099 IU\ml |
| Essen | Ratio of GMCs in Study Groups (Zagreb/Essen Schedules) on Days 7 and 42 as Measured by RVNA Geometric Mean Concentrations | Day 14(N=124,123) | 12 IU\ml |
| Essen | Ratio of GMCs in Study Groups (Zagreb/Essen Schedules) on Days 7 and 42 as Measured by RVNA Geometric Mean Concentrations | Day 7(N=125,123) | 1.74 IU\ml |
95% CI: [0.3, 0.48]ANOVA
95% CI: [0.86, 1.07]ANOVA