Safety and Immunogenicity of 2 Different Vaccination Schedules of Rabies and Japanese Encephalitis Vaccines in Healthy Adult Subjects

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Vaccines )
ClinicalTrials.gov Identifier:
NCT01662440
First received: August 2, 2012
Last updated: December 2, 2014
Last verified: December 2014
  Purpose
Establish non-inferiority of the immune response and evaluate the safety and tolerability of Rabies and Japanese Encephalitis (JE) vaccines given concomitantly or alone and according to either of 2 schedules for preexposure prophylaxis.

Condition Intervention Phase
Rabies
Japanese Encephalitis
Biological: Rabies
Biological: Japanese Encephalitis
Other: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: A Phase III, Multicenter, Observer-blind, Safety and Immunogenicity Study of Rabies Vaccine and Japanese Encephalitis Vaccine Administered Concomitantly and/or Separately According to 1 of 2 Different Preexposure Prophylaxis Schedules to Healthy Adult Subjects.

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Percentages of Subjects With RVNA Concentrations ≥0.5 IU/mL At 7 Days After Last Active Vaccination [ Time Frame: Day 7 after last active vaccination (day 15 - group that received accelerated schedule, day 36 - group that received conventional schedule) ] [ Designated as safety issue: No ]

    Immune response was measured as the percentage of subjects with rabies virus neutralizing antibody (RVNA) concentrations ≥0.5 IU/mL, evaluated using the rapid fluorescent focus inhibition test at day 7 after last active vaccination, i.e. the third out of four vaccinations given in the accelerated Rabies vaccine schedule and the fourth out of four vaccinations given in the conventional Rabies vaccine schedule.

    As per study design, this primary immunogenicity outcome measure aimed to demonstrate non-inferiority of R/JE - Acc Vs R - Conv.


  • Percentages of Subjects With PRNT50 Titer ≥1:10 At 28 Days After Last Active Vaccination [ Time Frame: Day 28 after last active vaccination (day 36 - group that received accelerated schedule, day 57 - group that received conventional schedule) ] [ Designated as safety issue: No ]

    Immune response was measured as the percentages of subjects with a titer of ≥1:10 in a 50% plaque reduction neutralization test (PRNT50) 28 days after last active vaccination, ie, the second out of three vaccinations given in the accelerated JE vaccine schedule and the third out of three vaccinations given in the conventional JE vaccine schedule.

    As per study design, this primary immunogenicity outcome measure aimed to demonstrate non-inferiority of R/JE - Acc Vs JE - Conv.



Secondary Outcome Measures:
  • RVNA Geometric Mean Concentrations (GMCs) At 28 Days After Last Active Vaccination [ Time Frame: Day 57 (28 days after last active vaccination) ] [ Designated as safety issue: No ]

    Immune response was measured as the RVNA GMCs 28 days after last active vaccination, ie, day 57 for all groups that received the conventional schedule.

    Data were adjusted using ANOVA model, as per protocol specification.


  • PRNT50 Geometric Mean Titers (GMTs) At 28 Days After Last Active Vaccination [ Time Frame: Day 57 (28 days after last active vaccination) ] [ Designated as safety issue: No ]

    Immune response was measured as the PRNT50 GMTs 28 days after last active vaccination, ie, day 57 for all groups that received the conventional schedule.

    Data were adjusted using ANOVA model, as per protocol specifications.


  • Percentages of Subjects With RVNA Concentrations ≥0.5 IU/mL At 28 Days After Last Active Vaccination [ Time Frame: Day 36 and day 57 (28 days after last active vaccination) ] [ Designated as safety issue: No ]

    Immune response was measured as the percentages of subjects with RVNA concentration ≥0.5 IU/mL 28 days after last active vaccination, ie, day 36 for the group that received the accelerated schedule and day 57 for the group that received the conventional schedule.

    As per study design, this secondary immunogenicity outcome measure aimed to demonstrate non-inferiority of R/JE - Acc Vs R - Conv.


  • Percentage of Subjects With PRNT50 Titer ≥1:10 At 7 Days After Last Active Vaccination [ Time Frame: Day 15 and day 36 (28 after last active vaccination) ] [ Designated as safety issue: No ]

    Immune response was measured as the percentage of subjects with PRNT50 titer of ≥1:10 7 days after last active vaccination, ie, day 15 for the group that received the accelerated schedule and day 36 for the group that received the conventional schedule.

    As per study design, this secondary immunogenicity outcome measure aimed to demonstrate non-inferiority of R/JE - Acc Vs JE - Conv.


  • Kinetics of Rabies Immune Response Measured as Percentage of Subjects With RVNA Concentration ≥0.5 IU/mL [ Time Frame: Day 1, 8, 15, 36, 57, 91, 181 and Day 366 ] [ Designated as safety issue: No ]
    To evaluate the kinetics of antibody response to Rabies vaccine, the immunogenicity was measured as the percentage of subjects with RVNA concentrations ≥0.5 IU/mL on days 1, 8, 15, 36, 57, 91, 181, and 366.

  • Kinetics of Rabies Immune Response Measured as the RVNA GMCs [ Time Frame: Day 1, 8, 15, 36, 57, 91, 181, and 366 ] [ Designated as safety issue: No ]
    To evaluate the kinetics of antibody response to Rabies vaccine, the immunogenicity was measured as the RVNA GMCs on days 1, 8, 15, 36, 57, 91, 181, and 366.

  • Kinetics of JE Immune Response Measured as Percentage of Subjects With PRNT50 Titers ≥1:10 [ Time Frame: Days 1, 15, 22, 36, 57, 91, 181 and 366 ] [ Designated as safety issue: No ]
    To evaluate the kinetics of antibody response to JE vaccine, the immunogenicity was measured as the percentage of subjects with PRNT50 titer ≥1:10 on days 1, 15, 22, 36, 57, 91, 181, and 366 (group that received JE vaccine as an accelerated schedule) and days 1, 36, 57, 181, and 366 (group that received JE vaccine as a conventional schedule).

  • Kinetics of JE Immune Response Measured as PRNT50 GMTs [ Time Frame: Day 1, 15, 22, 36, 57, 91, 181, and 366 (accelerated schedule) and day 1, 36, 57, 181, and 366 (conventional schedule) ] [ Designated as safety issue: No ]
    To evaluate the kinetics of antibody response to JE vaccine, the immunogenicity was measured as the PRNT50 GMTs on days 1, 15, 22, 36, 57, 91, 181, and 366 (group that received JE vaccine as an accelerated schedule) and days 1, 36, 57, 181, and 366 (group that received JE vaccine as a conventional schedule).

  • Number of Subjects Who Reported Solicited Local Adverse Events After Each Rabies Vaccination [ Time Frame: Day 1 through day 7 after each vaccination (on day 1, 4, 8 and 29) ] [ Designated as safety issue: No ]
    Safety was assessed as the number of subjects who reported solicited local adverse events (AEs) after each rabies vaccination given according to accelerated or conventional schedule as follows: from day 1 through day 7 (vaccination on day 1; all Rabies groups), day 4 through day 10 (vaccination on day 4; in R/JE - Acc group only), day 8 through day 14 (vaccination on day 8; all Rabies groups), or day 29 through day 35 (vaccination on day 29; R/JE - Conv and R - Conv groups).

  • Number of Subjects Who Reported Solicited Local AEs After Each JE Vaccination [ Time Frame: Day 1 through day 7 after each vaccination (on day 1, 8 and 29) ] [ Designated as safety issue: No ]
    Safety was assessed as the number of subjects who reported solicited local AEs after each JE vaccination given according to accelerated or conventional schedule as follow: from day 1 through day 7 (vaccination on day 1; all JE groups), day 8 through day 14 (vaccination on day 8; R/JE - Acc group only), or day 29 through day 35 (vaccination on day 29; R/JE - Con and JE - Conv groups).

  • Number of Subjects Who Reported Solicited Local AEs After Each Placebo Injection [ Time Frame: Day 1 through day 7 after each injection (day 1, 4, 8 and 29) ] [ Designated as safety issue: No ]
    Safety was assessed as the number of subjects who reported solicited local AEs after each placebo injection given according to accelerated and conventional schedule as follow: from day 1 through day 7 (injection on day 1; R - Conv and JE - Conv groups), day 4 through day 10 (injection on day 4; in R/JE - Conv, R - Conv and JE - Conv groups), day 8 through day 14 (injection on day 8; in R/JE - Conv, R - Conv and JE - Conv groups), and day 29 through day 35 (injection on day 29; R/JE - Acc, R - Con and JE - Conv groups).

  • Number of Subjects Who Reported Solicited Systemic AEs and Other Indicators of Reactogenicity After Each Vaccination [ Time Frame: Day 1 through day 7 after each vaccination (day 1, 4, 8 and 29) ] [ Designated as safety issue: No ]
    Safety was assessed as the number of subjects who reported solicited systemic AEs and other indicators of reactogenicity after each vaccination given according to accelerated and conventional schedule.

  • Numbers of Subjects Reporting Unsolicited AEs After Any Vaccination From Day 1 Through Day 57 [ Time Frame: Day 1 through Day 57 ] [ Designated as safety issue: No ]
    Safety was assessed as the number of subjects who reported unsolicited AEs after any vaccination given according to accelerated and conventional schedule.


Enrollment: 661
Study Start Date: August 2012
Study Completion Date: October 2013
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: R/JE - Conv
Subjects received Rabies and Japanese Encephalitis (JE) vaccines following the conventional schedule, ie, Rabies vaccination on days 1, 8, and 29, and placebo on day 4 in the right arm or leg; and JE vaccination on day 1 and 29, and placebo on day 8 in the left arm.
Biological: Rabies
Subjects received three doses of Rabies, whole virus vaccine (inactivated, Germany).
Biological: Japanese Encephalitis
Subjects received two doses of Japanese Encephalitis vaccine.
Other: Placebo
Subjects received either two, three, four or five doses of normal saline, 0.9% w/v sodium chloride depending on the vaccine group.
Experimental: R/JE - Acc
Subjects received Rabies and JE vaccines following the accelerated schedule, ie, Rabies vaccination on days 1, 4, and 8, and placebo on day 29 in the right arm or leg; and JE vaccination on days 1 and 8, and placebo on day 29 in the left arm.
Biological: Rabies
Subjects received three doses of Rabies, whole virus vaccine (inactivated, Germany).
Biological: Japanese Encephalitis
Subjects received two doses of Japanese Encephalitis vaccine.
Other: Placebo
Subjects received either two, three, four or five doses of normal saline, 0.9% w/v sodium chloride depending on the vaccine group.
Active Comparator: R - Conv
Subjects received Rabies vaccine following the conventional schedule, ie, Rabies vaccination on days 1, 8, and 29, and placebo on day 4 in the right arm or leg; and placebo on days 1, 8 and 29 in the left arm.
Biological: Rabies
Subjects received three doses of Rabies, whole virus vaccine (inactivated, Germany).
Other: Placebo
Subjects received either two, three, four or five doses of normal saline, 0.9% w/v sodium chloride depending on the vaccine group.
Active Comparator: JE - Conv
Subjects received JE vaccine following the conventional schedule, ie, placebo on days 1, 4, 8 and 29 in the right arm or leg; and JE vaccination on days 1 and 29 and placebo injection on day 8 in the left arm.
Biological: Japanese Encephalitis
Subjects received two doses of Japanese Encephalitis vaccine.
Other: Placebo
Subjects received either two, three, four or five doses of normal saline, 0.9% w/v sodium chloride depending on the vaccine group.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Males and females between 18 and 65 years of age (inclusive).
  2. Subjects who have given written consent.
  3. Individuals in good health as per investigator judgement.

Exclusion Criteria:

  1. If female, pregnancy or unwillingness to practice acceptable contraception.
  2. If female, pregnant or breast-feeding or any positive/indeterminate pregnancy test.
  3. Contraindication or precaution against Rabies and Japanese Encephalitis vaccination.
  4. Unable to comprehend and to follow all required study procedures for the whole period of the study.
  5. Participating in any other clinical trial 30 days prior to first study visit.
  6. History of previous rabies/rabies immunoglobulin and/or Japanese Encephalitis immunization.
  7. Receiving or planning to receive anti-malarial medications (e.g. Mefloquine) 14 days prior to Day 1 vaccination through Day 43.
  8. Received any other vaccines within 2 weeks prior to enrollment in this study or plan to receive any vaccine within 4 weeks from the study vaccines.
  9. Ever received blood, blood products and/or plasma derivatives or any parenteral immunoglobulin preparation in the past 12 weeks.
  10. Individuals who are part of study personnel or close family members conducting this study.
  11. Body temperature ≥38 degrees Celsius (≥ 100.4° F) within 3 days of intended study vaccination.
  12. Plans to travel within the next year to areas where Rabies and/or Japanese Encephalitis vaccine may be considered or offered. This includes but is not limited to India, Asia, Pacific-Rim, African countries.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01662440

Locations
Austria
Institute of Specific Prophylaxis and Tropical Medicine Center for Pathophysiology, Infectious Diseases and Immunology Medical University of Vienna
Kinderspitalgasse 15, Vienna, Austria, A-1090
Germany
Bernhard Nocht Institute for Tropical Medicine
Bernhard-Nocht-Strasse 74, Hamburg, Germany, D-20359
Switzerland
The University of Zurich
Rämistrasse 71, Zürich, Switzerland, CH-8006
Sponsors and Collaborators
Novartis Vaccines
Investigators
Study Chair: Novartis Vaccines and Diagnostics Novartis Vaccines
  More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Novartis Vaccines
ClinicalTrials.gov Identifier: NCT01662440     History of Changes
Other Study ID Numbers: V49_23  2011-005173-23 
Study First Received: August 2, 2012
Results First Received: October 6, 2014
Last Updated: December 2, 2014
Health Authority: Germany: Paul-Ehrlich-Institut
Austria: Agency for Health and Food Safety
Switzerland: Swissmedic

Keywords provided by Novartis:
Rabies
JE
accelerated schedule

Additional relevant MeSH terms:
Encephalitis
Rabies
Encephalitis, Japanese
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Rhabdoviridae Infections
Mononegavirales Infections
RNA Virus Infections
Virus Diseases
Encephalitis, Arbovirus
Arbovirus Infections
Encephalitis, Viral
Central Nervous System Viral Diseases
Flavivirus Infections
Flaviviridae Infections
Infectious Encephalitis
Central Nervous System Infections
Vaccines
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on August 25, 2016