A Clinical Study to Evaluate Immune Responses to Rabies Vaccine in Adults Who Received Different Primary Rabies Vaccination Regimens

Study Overview
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Brief Summary
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GlaxoSmithKline (GSK) Biologicals' Rabipur vaccine is indicated for active immunization against rabies in individuals of all ages. This includes pre-exposure prophylaxis (PrEP), in both primary series and booster dose, and post exposure prophylaxis.The aim of this extension study is to evaluate the long-term (up to approx.10 years) persistence and to assess the boostability of immune responses in subjects who received a primary series of accelerated or conventional rabies PrEP IM regimen No new subjects were enrolled in this study.

Detailed Description
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The protocol was amended to clarify: Timeframe between each yearly scheduled visit, Number of additional booster doses a subject may receive depending on the RVNA level reached, Premature withdrawal from the study Exclusion criteria on scheduled visits That only SAEs experienced by subjects who received the booster must be reported Rewording of the protocol.

Official Title
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A Phase 3, Open-label, Multicenter Study to Evaluate Long-term Immunogenicity and Boostability of Immune Responses in Adults Who Received Different Primary Vaccination Regimens of Pre-exposure Prophylaxis With Purified Chick-Embryo Cell Rabies Vaccine Administered Concomitantly or Separately From a Japanese Encephalitis Vaccine.

Conditions
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Virus Diseases

Intervention / Treatment
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* Biological: Rabipur
* Procedure: Blood sampling


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In order to participate in this study, all subjects must meet ALL of the inclusion criteria described. All individuals who were randomized to Conventional Rabies and JE vaccination or to Accelerated Rabies and JE vaccination or to Conventional Rabies groups during the parent study, who received the full PrEP regimen and completed the trial following V49_23 study protocol. Individuals who have voluntarily given written informed consent after the nature of the study has been explained according to local regulatory requirements, prior to study entry. Individuals who can comply with study procedures Males Or Females of non-childbearing potential Or Females of childbearing potential who are using an effective birth control method which they intend to use for at least 6 months after the booster vaccination. This criterion is applicable only for those subjects who receive a booster dose. Prior to receipt of booster vaccination during Ad hoc Clinic Visit, subjects must be evaluated to confirm that they are eligible. If subjects do not meet any of the original inclusion criteria listed above, they should not receive booster dose of rabies vaccine. Exclusion Criteria: Prior to extension study entry, each subject must not have: Completed the parent study V49_23 without receiving the full 3 rabies vaccine doses following the assigned pre-exposure prophylaxis regimen. History of exposure to suspected or confirmed rabid animal. Receipt of rabies immunoglobulins, rabies post exposure prophylaxis following completion of V49_23 study. Hypersensitivity, including allergy, to any component of vaccines, medicinal products or medical equipment whose use is foreseen in this study. Clinical conditions representing a contraindication to intramuscular vaccination and blood draws. Systemic administration of corticosteroids (PO/IV/IM) for more than 14 consecutive days within 90 days prior to informed consent or planning to receive them during the participation to the study. Administration of antineoplastic and immunomodulating agents or radiotherapy within 90 days prior to informed consent or planning to receive them during the participation to the study. Received immunoglobulins or any blood products within 180 days prior to informed consent or planning to receive them during the participation to the study. Study personnel as well as their immediate family or household member. Any other clinical condition that, in the opinion of the investigator, might pose additional risk to the subject due to participation in the study. Prior to Scheduled Visit, each subject must not have: History of exposure to suspected or confirmed rabid animal. Receipt of rabies immunoglobulins, non-study rabies vaccine following completion of V49_23 study. Hypersensitivity, including allergy, to any component of vaccines, medicinal products or medical equipment whose use is foreseen in this study. Clinical conditions representing a contraindication to intramuscular vaccination and blood draws. Systemic administration of corticosteroids (PO/IV/IM) for more than 14 consecutive days within 90 days prior to informed consent or planning to receive them during the participation to the study. Administration of antineoplastic and immunomodulating agents or radiotherapy within 90 days prior to informed consent or planning to receive them during the participation to the study. Received immunoglobulins or any blood products within 180 days prior to informed consent or planning to receive them during the participation to the study. Study personnel as well as their immediate family or household member. Any other clinical condition that, in the opinion of the investigator, might pose additional risk to the subject due to participation in the study. Prior to booster vaccination, each subject eligible for booster vaccination (i.e., subjects with RVNA concentrations <0.5 IU/mL at the first visit of this extension study [Day 1, Year 3] or at the following year visits [Year 4 to Year 9]) should be in good health status and must not have none of the following: Progressive, unstable or uncontrolled clinical conditions. Abnormal function of the immune system resulting from: Clinical conditions. Systemic administration of corticosteroids (PO/IV/IM) for more than 14 consecutive days within 90 days prior to the Ad hoc visit or receipt or planning to receive them during the participation to the study. Administration of antineoplastic and immunomodulating agents or radiotherapy within 90 days prior to the Ad hoc visit or receipt or planning to receive them during the participation to the study. Receipt of non-study rabies vaccine. Receipt of any other vaccines within 28 days prior to the booster dose or planning to receive any vaccine within 28 days from the booster dose. Receipt of any investigational or non-registered medicinal product within 14 days before booster dose till next Scheduled Clinic Visit after booster dose administration. Receipt of anti-malarial medications within 14 days before booster dose till next Scheduled Clinic Visit after booster dose administration. Prior to receipt of booster study vaccination, subjects must be evaluated to confirm that they are in good health and they are eligible for subsequent vaccination. If subjects meet any of the original exclusion criteria listed above, they should not receive additional vaccinations.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Conv-R/JE Group<br>Subjects who completed the Rabies PrEP regimen on days 1,8 and 29 and JE primary series regimen on days 1 and 29 in the parent study V49_23 were enrolled in the Conv-R/JE Group and received a single booster dose of the PCEC rabies vaccine in this extension study. | Biological: Rabipur<br>* Subjects in all the groups received Rabipur vaccine booster dose, administered intramuscularly in the deltoid region of the non-dominant arm<br>Procedure: Blood sampling<br>* Blood samples were drawn from all subjects at day 1 and then at subsequent year intervals from extension study day 1 onwards.<br>|
| Experimental: Acc-R/JE Group<br>Subjects who completed the Rabies PrEP regimen on days 1, 4 and 8 and JE primary series regimen on days 1 and 8 in the parent study V49_23 were enrolled in the Acc-R/JE Group and received a single booster dose of the PCEC rabies vaccine in this extension study. | Biological: Rabipur<br>* Subjects in all the groups received Rabipur vaccine booster dose, administered intramuscularly in the deltoid region of the non-dominant arm<br>Procedure: Blood sampling<br>* Blood samples were drawn from all subjects at day 1 and then at subsequent year intervals from extension study day 1 onwards.<br>|
| Experimental: Conv-R Group<br>Subjects who completed the Rabies PrEP regimen on days 1,8 and 29 in the parent study V49_23 were enrolled into the Conv-R Group and received a single booster dose of the PCEC rabies vaccine in this extension study. | Biological: Rabipur<br>* Subjects in all the groups received Rabipur vaccine booster dose, administered intramuscularly in the deltoid region of the non-dominant arm<br>Procedure: Blood sampling<br>* Blood samples were drawn from all subjects at day 1 and then at subsequent year intervals from extension study day 1 onwards.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects reporting serious adverse events (SAEs) after a booster dose of PCEC (purified chick embryo cell culture) rabies vaccine | An SAE is defined as any untoward medical occurrence that at any dose results in one or more of the following: Death Is life-threatening Requires or prolonged hospitalization. Persistent or significant disability/incapacity Congenital anomaly/or birth defect. An important and significant medical event that may not be immediately life threatening or resulting in death or hospitalization but, based upon appropriate medical judgment, may jeopardize the subject or may require intervention to prevent one of the other outcomes listed above. Safety is assessed as the number of subjects reporting SAEs after a booster dose of PCEC rabies vaccine following a primary series of accelerated or conventional rabies PrEP (pre-exposure) IM (intramuscular) regimen in the parent study V49_23. | From the time of booster dose administration(Day 1 in extension study)until completion of safety follow-up period(day of next Scheduled Clinic Visit after booster dose/on date of Early Termination Visit, whichever is earlier,assessed up to year 10) | 
| Time to first RVNA (Rabies Virus Neutralizing Antibodies) concentrations <0.5 IU/mL. | The time until RVNA concentrations drop below 0.5 IU/mL is calculated to compare the long-term persistence of antibody responses in subjects who received a primary series of accelerated or conventional rabies PrEP IM regimen in the parent study V49_23 | Throughout the study duration (From 1 year after primary dose schedule in parent study V49_23 to year 10). | 
| RVNA concentrations in terms of Geometric Mean Concentrations (GMCs) 7 days after the booster dose. | Antibody concentrations at 7 days after booster dose are measured in terms of GMCs. | At 7 days after booster dose | 
| RVNA Geometric Mean Ratios (GMRs) at 7 days after the booster dose vs. antibody concentration before the booster dose. | For subjects receiving a booster dose, analysis of boostability is conducted 7 days after administration of the booster dose by providing GMRs and associated CIs, considering the antibody value at the time of booster dose administration as baseline. | At 7 days after booster dose versus before booster dose administration (baseline- 6 months before booster dose). | 
| Percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL as measured by RFFIT (Rapid Fluorescent Focus Inhibition Test) analysis at 7 days after booster dose. | The percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL are measured at 7 days after booster dose | At 7 days after booster dose | 
| Percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL as measured by RFFIT (Rapid Fluorescent Focus Inhibition Test) analysis. | The percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL are measured at year 3 after primary series of vaccination. | At year 3 after primary series of vaccine administration. | 
| Percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL as measured by RFFIT (Rapid Fluorescent Focus Inhibition Test) analysis. | The percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL are measured at year 4 after primary series of vaccination. | At year 4 after primary series of vaccine administration. | 
| Percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL as measured by RFFIT (Rapid Fluorescent Focus Inhibition Test) analysis. | The percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL are measured at year 5 after primary series of vaccination. | At year 5 after primary series of vaccine administration. | 
| Percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL as measured by RFFIT (Rapid Fluorescent Focus Inhibition Test) analysis. | The percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL are measured at year 6 after primary series of vaccination. | At year 6 after primary series of vaccine administration. | 
| Percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL as measured by RFFIT (Rapid Fluorescent Focus Inhibition Test) analysis. | The percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL are measured at year 7 after primary series of vaccination. | At year 7 after primary series of vaccine administration. | 
| Percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL as measured by RFFIT (Rapid Fluorescent Focus Inhibition Test) analysis. | The percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL are measured at year 8 after primary series of vaccination. | At year 8 after primary series of vaccine administration. | 
| Percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL as measured by RFFIT (Rapid Fluorescent Focus Inhibition Test) analysis. | The percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL are measured at year 9 after primary series of vaccination. | At year 9 after primary series of vaccine administration. | 
| Percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL as measured by RFFIT (Rapid Fluorescent Focus Inhibition Test) analysis. | The percentages of subjects with RVNA concentrations ≥ 0.5 IU/mL are measured at year 10 after primary series of vaccination. | At year 10 after primary series of vaccine administration. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| RVNA Geometric Mean Concentrations (GMCs) | The RVNA GMCs with the 95% CI are calculated at Year 3 after primary series of vaccination | At year 3 after primary series of vaccine administration. | 
| RVNA Geometric Mean Concentrations (GMCs) | The RVNA GMCs with the 95% CI are calculated at Year 4 after primary series of vaccination | At year 4 after primary series of vaccine administration. | 
| RVNA Geometric Mean Concentrations (GMCs) | The RVNA GMCs with the 95% CI are calculated at Year 5 after primary series of vaccination | At year 5 after primary series of vaccine administration. | 
| RVNA Geometric Mean Concentrations (GMCs) | The RVNA GMCs with the 95% CI are calculated at Year 6 after primary series of vaccination | At year 6 after primary series of vaccine administration. | 
| RVNA Geometric Mean Concentrations (GMCs) | The RVNA GMCs with the 95% CI are calculated at Year 7 after primary series of vaccination | At year 7 after primary series of vaccine administration. | 
| RVNA Geometric Mean Concentrations (GMCs) | The RVNA GMCs with the 95% CI are calculated at Year 8 after primary series of vaccination | At year 8 after primary series of vaccine administration. | 
| RVNA Geometric Mean Concentrations (GMCs) | The RVNA GMCs with the 95% CI are calculated at Year 9 after primary series of vaccination | At year 9 after primary series of vaccine administration. | 
| RVNA Geometric Mean Concentrations (GMCs) | The RVNA GMCs with the 95% CI are calculated at Year 10 after primary series of vaccination | At year 10 after primary series of vaccine administration. | 
| Reverse Cumulative Distribution Plots (RCDPs) for subjects with RVNA concentrations ≥0.5 IU/mL. | The RCDPs are provided by treatment group, at year 3 | At year 3 | 
| RCDPs for subjects with RVNA concentrations ≥0.5 IU/mL. | The RCDPs are provided by treatment group, at year 4 | At year 4 | 
| RCDPs for subjects with RVNA concentrations ≥0.5 IU/mL. | The RCDPs are provided by treatment group, at year 5 | At year 5 | 
| RCDPs for subjects with RVNA concentrations ≥0.5 IU/mL. | The RCDPs are provided by treatment group, at year 6 | At year 6 | 
| RCDPs for subjects with RVNA concentrations ≥0.5 IU/mL. | The RCDPs are provided by treatment group, at year 7 | At year 7 | 
| RCDPs for subjects with RVNA concentrations ≥0.5 IU/mL. | The RCDPs are provided by treatment group, at year 8 | At year 8 | 
| RCDPs for subjects with RVNA concentrations ≥0.5 IU/mL. | The RCDPs are provided by treatment group, at year 9 | At year 9 | 
| RCDPs for subjects with RVNA concentrations ≥0.5 IU/mL. | The RCDPs are provided by treatment group, at year 10 | At year 10 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rabies disease, Pre-exposure (PrEP) or post exposure prophylaxis (PEP), Long-term Immunogenicity