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

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ClinicalTrials.gov Identifier: NCT02177032
Recruitment Status : Completed
First Posted : June 27, 2014
Results First Posted : April 7, 2017
Last Update Posted : April 7, 2017
Sponsor:
Collaborator:
Novartis Vaccines
Information provided by (Responsible Party):
Novartis

Tracking Information
First Submitted Date  ICMJE June 24, 2014
First Posted Date  ICMJE June 27, 2014
Results First Submitted Date  ICMJE August 18, 2016
Results First Posted Date  ICMJE April 7, 2017
Last Update Posted Date April 7, 2017
Study Start Date  ICMJE June 2014
Actual Primary Completion Date October 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 21, 2017)
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) [ Time Frame: Study day 50 (D50) ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 26, 2014)
Percentage of subjects with RVNA titer ≥ 0.5 IU/mL at day 50 and group differences. [ Time Frame: study day 50 ]
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.
Change History Complete list of historical versions of study NCT02177032 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 21, 2017)
  • 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 [ Time Frame: Study Day 50 ]
    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.
  • 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 [ Time Frame: At Days 8, 15, 91, 181 and 366 ]
    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.
  • 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 [ Time Frame: At Days 8, 15, 91, 181 and 366 ]
    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.
  • Geometric Mean Rabies Virus Neutralizing Antibody (RVNA) Concentration and Vaccine Group Differences in Adult Subjects, ≥ 18 Years of Age [ Time Frame: At Days 8, 15, 50, 91, 181 and 366 ]
    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)
  • Percentages of Subjects With Anti-RVNA Titer ≥0.5 IU/mL in Adult Subjects, ≥ 18 Years of Age [ Time Frame: At Days 8, 15,50, 91, 181 and 366 ]
    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)
  • Geometric Mean Rabies Virus Neutralizing Antibody (RVNA) Concentration in Children and Adult Subjects, ≥ 1 Years of Age [ Time Frame: At Days 8, 15, 50, 91, 181 and 366 ]
    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
  • Percentages of Subjects With Anti-RVNA Titer ≥0.5 IU/mL in Children and Adult Subjects, ≥ 1 Years of Age [ Time Frame: At Days 8, 15, 50, 91, 181 and 366 ]
    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
  • Number of Subjects Who Reported Solicited Local and Systemic Adverse Events After Any Vaccination [ Time Frame: 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 Who Reported Solicited Local and Systemic Adverse Events After Any Vaccination
  • Number of Subjects Reporting Unsolicited Adverse Events (AEs) [ Time Frame: Day 1 to Day 366 ]
    Safety was assessed in terms of the Number of Subjects Reporting Unsolicited Adverse Events (AEs)
  • Geometric Mean Rabies Virus Neutralizing Antibody (RVNA) Concentration ≥0.5 IU/mL and Vaccine Group Differences in Adult Subjects, ≥ 18 Years of Age [ Time Frame: At Days 8, 15, 50, 91, 181 and 366 ]
    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
  • Percentages of Subjects With Anti-RVNA Titer ≥0.5 IU/mL in Adult Subjects, ≥ 18 Years of Age [ Time Frame: At Days 8, 15,50, 91, 181 and 366 ]
    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
Original Secondary Outcome Measures  ICMJE
 (submitted: June 26, 2014)
  • RVNA Geometric Mean Concentration at day 50 and between-group ratio of GMCs (4-sites, 1-week versus 2-sites, TRC) in the whole study population [ Time Frame: study day 50 ]
    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.
  • RVNA GMCs and percentage of subjects with RVNA titer ≥ 0.5 IU/mL at days 8, 15, 91, 181 and 366 and group differences (4-sites, 1-week versus 2-sites, TRC) in the whole study population [ Time Frame: study days 8, 15, 91, 181 and 366 ]
    RVNA GMCs and 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.
  • RVNA GMCs and percentage of subjects with RVNA titer ≥ 0.5 IU/mL at study days 8, 15, 91, 181, and 366 following administration of new 4-sites, 1-week ID regimen of rabies vaccine, with HRIG and without HRIG administration, in adult subjects. [ Time Frame: study days 8, 15, 91, 181 and 366 ]
    RVNA GMCs and 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)
  • RVNA GMCs and percentage of subjects with RVNA titer ≥ 0.5 IU/mL at study days 8, 15, 91, 181, and 366 following administration of of the 2 ID rabies vaccine regimens (4-sites, 1-week and 2-sites, TRC), with HRIG, in adult subjects. [ Time Frame: study days 8, 15, 91, 181, and 366 ]
  • RVNA GMCs and percentage of subjects with RVNA titer ≥ 0.5 IU/mL at study days 8, 15, 91, 181, and 366 following administration of of the 2 ID rabies vaccine regimens (4-sites, 1-week and 2-sites, TRC), without HRIG, in the whole study population. [ Time Frame: study days 8, 15, 91, 181, and 366 ]
  • Percentages of subjects reporting solicited local and systemic adverse events (AEs), and associated medications, will be collected [ Time Frame: 7 days following administration of each study vaccination or until time of next vaccination ]
  • Percentages of subjects reporting AEs [ Time Frame: All reported SAEs and AEs leading to subject withdrawal, and associated medications, were collected up to 366 days after first vaccination ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Immunogenicity of Two Intradermal Rabies Vaccine Regimens Administered With and Without Human Rabies Immunoglobulin in Subjects ≥ 1 Years of Age
Official Title  ICMJE 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.
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Rabies Infection
Intervention  ICMJE
  • Biological: Rabies vaccine
    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).
  • Biological: Rabies vaccines + Rabies immunoglobulins
    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.
  • Biological: Rabies vaccine
    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).
  • Biological: Rabies vaccines + Rabies immunoglobulins
    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.
Study Arms  ICMJE
  • Experimental: 4-sites, 1-week without HRIG
    PCEC rabies vaccine, administered ID according to the "4-sites, 1-week" regimen
    Intervention: Biological: Rabies vaccine
  • Experimental: 4-sites, 1-week with HRIG
    PCEC rabies vaccine, administered ID to adults, according to the "4-sites, 1-week" regimen plus HRIG
    Intervention: Biological: Rabies vaccines + Rabies immunoglobulins
  • Active Comparator: 2-sites, TRC without HRIG
    PCEC rabies vaccine, administered ID according to the "2-sites, TRC" regimen
    Intervention: Biological: Rabies vaccine
  • Active Comparator: 2-sites, TRC with HRIG
    PCEC rabies vaccine, administered ID to adults , according to the "2-sites, TRC" regimen plus HRIG
    Intervention: Biological: Rabies vaccines + Rabies immunoglobulins
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 5, 2015)
885
Original Estimated Enrollment  ICMJE
 (submitted: June 26, 2014)
876
Actual Study Completion Date  ICMJE August 2015
Actual Primary Completion Date October 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Healthy males and females ≥ 1 years of age
  2. Individuals/ individual's parents or legal guardians who have given written consent
  3. Individuals in good health
  4. Individuals who can comply with study procedures

Exclusion Criteria:

  1. Behavioral or cognitive impairment or psychiatric disease.
  2. Unable to comprehend and to follow all required study procedures for the whole period of the study.
  3. History of illness or with an ongoing illness that may pose additional risk to the individual if he/she participates in the study.
  4. Individuals ≥ 1 to ≤ 17 years of age, who have or ever had a malignancy.
  5. 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.
  6. Known or suspected impairment of the immune system (including but not limited to HIV, autoimmune disorders, immunosuppressive therapy as applicable).
  7. Female of childbearing potential who has not used any of the "acceptable contraceptive methods" for at least 2 months prior to study entry.
  8. Female of childbearing potential, refusal to use an "acceptable birth control method" through day 50.
  9. Female of childbearing potential, with a positive pregnancy test prior to enrollment.
  10. Received blood, blood products and/or plasma derivatives or any parenteral immunoglobulin preparation in the previous 12 weeks.
  11. Allergic to any of the vaccine components.
  12. Allergic to any of the human rabies immunoglobulin components.
  13. Contraindication or precaution against rabies vaccination.
  14. Contraindication or precaution against man rabies immunoglobulin administration.
  15. Planning to receive anti-malaria medications (e.g. Mefloquine) 14 days prior to day 1 vaccination through day 50.
  16. 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.
  17. 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.
  18. Body temperature ≥ 38.0°C (≥ 100.4°F) within 3 days of intended study vaccination.
  19. Received rabies vaccines or rabies immunoglobulin or have been exposed to rabies.
  20. Part of the study personnel or immediate family members of study personnel conducting this study.
  21. Current or history of drug or alcohol abuse within the past 2 years.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 1 Year and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Philippines,   Thailand
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02177032
Other Study ID Numbers  ICMJE V49_30
2013-CT0191 ( Registry Identifier: registry.healthresearch.ph )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Novartis
Study Sponsor  ICMJE Novartis
Collaborators  ICMJE Novartis Vaccines
Investigators  ICMJE
Study Chair: Novartis Vaccines Novartis Vaccines
PRS Account Novartis
Verification Date February 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP