Safety and Immunogenicity of Two Intradermal Rabies Vaccine Regimens Administered With and Without Human Rabies Immunoglobulin in Subjects ≥ 1 Years of Age

Study Overview
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Brief Summary
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Demonstrate non-inferiority of the immune response between new versus the currently recommended intradermal regimens of rabies vaccine when administered with or without rabies immunoglobulins in healthy subjects ≥ 1 years of age.

Official Title
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Phase 3, Randomized, Stratified, Open Label, Multicenter, Controlled Clinical Study to Evaluate Safety and Immunogenicity of a Rabies Vaccine Administered, With and Without Human Rabies Immunoglobulin, Using the New 4-sites, 1-week Intradermal Regimen for Postexposure Prophylaxis Compared to the Currently Recommended 2-sites, TRC Intradermal Regimen in Children and Adults Subjects.

Conditions
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Rabies Infection

Intervention / Treatment
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* Biological: Rabies vaccine
* Biological: Rabies vaccines + Rabies immunoglobulins
* Biological: Rabies vaccine
* Biological: Rabies vaccines + Rabies immunoglobulins


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males and females ≥ 1 years of age Individuals/ individual's parents or legal guardians who have given written consent Individuals in good health Individuals who can comply with study procedures Exclusion Criteria: Behavioral or cognitive impairment or psychiatric disease. Unable to comprehend and to follow all required study procedures for the whole period of the study. History of illness or with an ongoing illness that may pose additional risk to the individual if he/she participates in the study. Individuals ≥ 1 to ≤ 17 years of age, who have or ever had a malignancy. Individuals ≥ 18 years of age, who have or who within the last 5 years, have had a malignancy (excluding nonmelanotic skin cancer) or lymphoproliferative disorder. Known or suspected impairment of the immune system (including but not limited to HIV, autoimmune disorders, immunosuppressive therapy as applicable). Female of childbearing potential who has not used any of the acceptable contraceptive methods for at least 2 months prior to study entry. Female of childbearing potential, refusal to use an acceptable birth control method through day 50. Female of childbearing potential, with a positive pregnancy test prior to enrollment. Received blood, blood products and/or plasma derivatives or any parenteral immunoglobulin preparation in the previous 12 weeks. Allergic to any of the vaccine components. Allergic to any of the human rabies immunoglobulin components. Contraindication or precaution against rabies vaccination. Contraindication or precaution against man rabies immunoglobulin administration. Planning to receive anti-malaria medications (e.g. Mefloquine) 14 days prior to day 1 vaccination through day 50. Participating in any clinical trial with another investigational product 30 days prior to first study visit or intent to participate in another clinical study at any time during the conduct of this study. Received any other vaccines within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to enrollment in this study or who are planning to receive any vaccine within 28 days from the study vaccines. Body temperature ≥ 38.0°C (≥ 100.4°F) within 3 days of intended study vaccination. Received rabies vaccines or rabies immunoglobulin or have been exposed to rabies. Part of the study personnel or immediate family members of study personnel conducting this study. Current or history of drug or alcohol abuse within the past 2 years.

Ages Eligible for Study
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Minimum Age: 1 Year

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 4-sites, 1-week without HRIG<br>PCEC rabies vaccine, administered ID according to the 4-sites, 1-week regimen | Biological: Rabies vaccine<br>* 12 doses of the PCEC rabies vaccine, administered ID (0.1mL for each injection) according to the 4-sites, 1-week regimen (i.e. 4 doses of vaccine; in both deltoids and anterolateral thigh areas, administered on days 1, 4, and 8).<br>|
| Experimental: 4-sites, 1-week with HRIG<br>PCEC rabies vaccine, administered ID to adults, according to the 4-sites, 1-week regimen plus HRIG | Biological: Rabies vaccines + Rabies immunoglobulins<br>* 12 doses of the PCEC rabies vaccine, administered ID (0.1mL for each injection) to adults only, according to the 4-sites, 1-week regimen (i.e. 4 doses of vaccine; in both deltoids and anterolateral thigh areas, administered on days 1, 4, and 8). HRIG will be administered on day 1 (before the first dose of the vaccine) in a dose of 20 IU/kg body weight intramuscularly into the gluteal muscle.<br>|
| Active Comparator: 2-sites, TRC without HRIG<br>PCEC rabies vaccine, administered ID according to the 2-sites, TRC regimen | Biological: Rabies vaccine<br>* 8 doses of the PCEC rabies vaccine, administered ID (0.1ml for each injection) according to the 2-sites, TRC, updated Thai Red Cross regimen (i.e. 2 doses of vaccine; in both deltoids, administered on days 1, 4, 8, and 29).<br>|
| Active Comparator: 2-sites, TRC with HRIG<br>PCEC rabies vaccine, administered ID to adults , according to the 2-sites, TRC regimen plus HRIG | Biological: Rabies vaccines + Rabies immunoglobulins<br>* 8 doses of the PCEC rabies vaccine, administered ID (0.1ml for each injection) to adults only, according to the 2-sites, TRC, updated Thai Red Cross regimen (i.e. 2 doses of vaccine; in both deltoids, administered on days 1, 4, 8, and 29). HRIG will be administered on day 1 (before the first dose of the vaccine) in a dose of 20 IU/kg body weight intramuscularly into the gluteal muscle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentages of Subjects With RVNA Titer >= 0.5 and Vaccine Group Differences (4-sites, 1-week to That of 2-sites, TRC ID PEP Regimen of the PCEC Rabies Vaccine With or Without HRIG Administration) | Vaccine group differences are calculated assuming a binomial distribution and the associated confidence interval for the differences in percentage was based on M-N method. Non-inferiority of the immune response of the new 4-sites, 1-week ID PEP regimen of the PCEC vaccine, with or without HRIG administration, to that of the currently recommended 2-sites, TRC ID PEP regimen of the PCEC rabies vaccine with or without HRIG administration, as measured by the percentage of subjects with RVNA titer ≥ 0.5 IU/ml at day 50 in the whole study population. | Study day 50 (D50) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Rabies Virus Neutralizing Antibody (RVNA) Concentration and Between-group (2 ID Rabies Vaccine Regimens (4-sites, 1-week and 2-sites, TRC) With or Without HRIG) Ratio of GMCs | Immunogenicity was assessed in terms of Geometric Mean Rabies Virus Neutralizing Antibody (RVNA) Concentration in Children and Adult Subjects, ≥ 1 Years of Age at day 50 The GMCs, GMRs (i.e., within group ratio) and associated two sided 95% confidence intervals for each group were computed by exponentiating (base 10) of the least square means of the logarithmically transformed (base 10) concentration (and their differences) and the 95% CIs obtained from an Analysis of variance (ANOVA) with vaccine regimen, age strata and center as factors. Non-inferiority of the immune response between the 2 ID rabies vaccine regimens (4-sites, 1-week and 2-sites, TRC) with or without HRIG administration as measured by RVNA GMCs at day 50 in the whole study population. | Study Day 50 | 
| Geometric Mean Rabies Virus Neutralizing Antibody Concentration at Days 8, 15, 91, 181 and 366 & Between-group (2 ID Rabies Vaccine Regimens (4-sites,1-week & 2-sites, TRC) With or Without HRIG) Ratio of GMCs in Children & Adult Subjects,≥ 1 Years of Age | Immunogenicity was assessed in terms of the Geometric Mean Rabies Virus Neutralizing Antibody (RVNA) Concentration at Days 8, 15, 91, 181 and 366 in Children and Adult Subjects, ≥ 1 Years of Age The GMCs, GMRs (i.e., within group ratio) and associated two sided 95% confidence intervals for each group were computed by exponentiating (base 10) of the least square means of the logarithmically transformed (base 10) concentration (and their differences) and the 95% CIs obtained from an Analysis of variance (ANOVA) with vaccine regimen, age strata and center as factors. Non-inferiority of the immune response between the 2 ID rabies vaccine regimens (4-sites, 1-week and 2-sites, TRC) with or without HRIG administration as measured by RVNA GMCs at day 50 in the whole study population. | At Days 8, 15, 91, 181 and 366 | 
| Percentages of Subjects With Anti-RVNA Titer ≥0.5 IU/mL at Days 8, 15, 91, 181 and 366 in Children and Adult Subjects and Vaccine Group Differences (2 ID Rabies Vaccine Regimens (4-sites, 1-week and 2-sites, TRC), With or Without HRIG), ≥ 1 Years of Age | Vaccine group differences are calculated assuming a binomial distribution and the associated confidence interval for the differences in percentage was based on M-N method. RVNA percentage of subjects with RVNA titer ≥ 0.5 IU/mL at study days 8, 15, 91, 181, and 366 following administration of the 2 ID rabies vaccine regimens (4-sites, 1-week and 2-sites, TRC), with or without HRIG, in the whole study population. | At Days 8, 15, 91, 181 and 366 | 
| Geometric Mean Rabies Virus Neutralizing Antibody (RVNA) Concentration and Vaccine Group Differences in Adult Subjects, ≥ 18 Years of Age | Immunogenicity was assessed in terms of the Geometric Mean Rabies Virus Neutralizing Antibody (RVNA) Concentration at Days 8, 15, 50,91, 181 and 366 in Adult Subjects, ≥ 18 Years of Age. RVNA GMCs with RVNA titer ≥ 0.5 IU/mL at days 8, 15, 50, 91, 181 and 366 and group differences (4-sites,1-week without HRIG versus 4-sites,1-week with HRIG; 4-sites,1-week with HRIG versus 2-sites,TRC with HRIG; 4-sites,1-week without HRIG versus 2-sites, TRC without HRIG) | At Days 8, 15, 50, 91, 181 and 366 | 
| Percentages of Subjects With Anti-RVNA Titer ≥0.5 IU/mL in Adult Subjects, ≥ 18 Years of Age | Immunogenicity was assessed in terms of the Percentages of Subjects With Anti-RVNA concentration ≥0.5 IU/mL at Days 8, 15, 50, 91, 181 and 366 in Adult Subjects, ≥ 18 Years of Age. Percentage of subjects with RVNA titer ≥ 0.5 IU/mL at days 8, 15, 50, 91, 181 and 366 and group differences (4-sites,1-week without HRIG versus 4-sites,1-week with HRIG; 4-sites,1-week with HRIG versus 2-sites,TRC with HRIG; 4-sites,1-week without HRIG versus 2-sites, TRC without HRIG) | At Days 8, 15,50, 91, 181 and 366 | 
| Geometric Mean Rabies Virus Neutralizing Antibody (RVNA) Concentration in Children and Adult Subjects, ≥ 1 Years of Age | Immunogenicity was assessed in terms of the Geometric Mean Rabies Virus Neutralizing Antibody (RVNA) Concentration at Days 8, 15, 50, 91, 181 and 366 in Children and Adult Subjects, ≥ 1 Years of Age | At Days 8, 15, 50, 91, 181 and 366 | 
| Percentages of Subjects With Anti-RVNA Titer ≥0.5 IU/mL in Children and Adult Subjects, ≥ 1 Years of Age | Immunogenicity was assessed in terms of the Percentages of Subjects With Anti-RVNA concentration ≥0.5 IU/mL at Days 8, 15, 50, 91, 181 and 366 in Children and Adult Subjects, ≥ 1 Years of Age | At Days 8, 15, 50, 91, 181 and 366 | 
| Number of Subjects Who Reported Solicited Local and Systemic Adverse Events After Any Vaccination | Number of subjects Who Reported Solicited Local and Systemic Adverse Events After Any Vaccination | From day 1 to day 3; from day 4 to day 7; from day 8 to day 14; from day 29 to day 35(2-sites, TRC PEP, ID regimen) | 
| Number of Subjects Reporting Unsolicited Adverse Events (AEs) | Safety was assessed in terms of the Number of Subjects Reporting Unsolicited Adverse Events (AEs) | Day 1 to Day 366 | 
| Geometric Mean Rabies Virus Neutralizing Antibody (RVNA) Concentration ≥0.5 IU/mL and Vaccine Group Differences in Adult Subjects, ≥ 18 Years of Age | Immunogenicity was assessed in terms of the Geometric Mean Rabies Virus Neutralizing Antibody (RVNA) Concentration ≥0.5 IU/mL at Days 8, 15, 50,91, 181 and 366 in Adult Subjects, ≥ 18 Years of Age | At Days 8, 15, 50, 91, 181 and 366 | 
| Percentages of Subjects With Anti-RVNA Titer ≥0.5 IU/mL in Adult Subjects, ≥ 18 Years of Age | Immunogenicity was assessed in terms of the number of subjects With Anti-RVNA concentration ≥0.5 IU/mL at Days 8, 15, 50, 91, 181 and 366 in Adult Subjects, ≥ 18 Years of Age | At Days 8, 15,50, 91, 181 and 366 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rabies vaccines, intradermal, human rabies immunoglobulins