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

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ClinicalTrials.gov Identifier: NCT01662440
Recruitment Status : Completed
First Posted : August 10, 2012
Results First Posted : December 8, 2014
Last Update Posted : December 8, 2014
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Vaccines )

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Prevention
Conditions Rabies
Japanese Encephalitis
Interventions Biological: Rabies
Biological: Japanese Encephalitis
Other: Placebo
Enrollment 661
Recruitment Details Subjects were enrolled from five sites in Germany, one site in Austria, and one site in Switzerland.
Pre-assignment Details All subjects were included in the trial.
Arm/Group Title R/JE – Conv R/JE – Acc R – Conv JE – Conv
Hide Arm/Group Description Subjects received Rabies and Japanese Encephalitis (JE) vaccines, 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. Subjects received Rabies and JE vaccines, 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. Subjects received Rabies vaccine, 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. Subjects received JE vaccine, 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.
Period Title: Overall Study
Started 167 217 221 56
Completed 158 211 215 52
Not Completed 9 6 6 4
Reason Not Completed
Adverse Event             1             0             0             1
Death             0             1             0             0
Lost to Follow-up             2             2             4             1
Subject moved to another country.             0             1             0             0
Protocol Violation             1             0             0             0
Withdrawal by Subject             5             2             2             2
Arm/Group Title R/JE – Conv R/JE – Acc R – Conv JE – Conv Total
Hide Arm/Group Description Subjects received Rabies and JE vaccines, 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. Subjects received Rabies and JE vaccines, 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. Subjects received Rabies vaccine, 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. Subjects received JE vaccine, 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. Total of all reporting groups
Overall Number of Baseline Participants 167 217 221 56 661
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Year
Number Analyzed 167 participants 217 participants 221 participants 56 participants 661 participants
37.3  (13.4) 36.8  (12.7) 35.7  (12.6) 38.8  (13.3) 36.7  (12.9)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 167 participants 217 participants 221 participants 56 participants 661 participants
Female
76
  45.5%
128
  59.0%
125
  56.6%
30
  53.6%
359
  54.3%
Male
91
  54.5%
89
  41.0%
96
  43.4%
26
  46.4%
302
  45.7%
1.Primary Outcome
Title Percentages of Subjects With RVNA Concentrations ≥0.5 IU/mL At 7 Days After Last Active Vaccination
Hide Description

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.

Time Frame Day 7 after last active vaccination (day 15 – group that received accelerated schedule, day 36 – group that received conventional schedule)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on the per-protocol (PP) dataset, ie, the subjects who received the vaccine correctly, provided evaluable serum samples at the relevant time points, and had no major protocol violations as defined prior to unblinding.
Arm/Group Title R/JE – Acc R – Conv
Hide Arm/Group Description:
Subjects received Rabies and JE vaccines, 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.
Subjects received Rabies vaccine, 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.
Overall Number of Participants Analyzed 209 207
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentages of subjects
100
(97 to 100)
100
(97 to 100)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection R/JE – Acc, R – Conv
Comments To establish non-inferiority of the immune response of Rabies vaccine (administered concomitantly with JE vaccine) accelerated schedule as compared to conventional schedule at 7 days after last active vaccination.
Type of Statistical Test Non-Inferiority or Equivalence
Comments The immune response of accelerated schedule of the Rabies vaccine considered non-inferior to the conventional schedule if the lower bound of the two-sided 97.5% Confidence Intervals (CI) of the difference in the percentages of subjects with RVNA titer ≥0.5 IU/mL measured 7 days after last active vaccination is greater than -5.
Method of Estimation Estimation Parameter Difference in percentages of subjects
Estimated Value 0
Confidence Interval (2-Sided) 97.5%
-2.8 to 2.8
Estimation Comments [Not Specified]
2.Primary Outcome
Title Percentages of Subjects With PRNT50 Titer ≥1:10 At 28 Days After Last Active Vaccination
Hide Description

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.

Time Frame Day 28 after last active vaccination (day 36 – group that received accelerated schedule, day 57 – group that received conventional schedule)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on the PP dataset.
Arm/Group Title R/JE – Acc JE – Conv
Hide Arm/Group Description:
Subjects received Rabies and JE vaccines, 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.
Subjects received JE vaccine, 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.
Overall Number of Participants Analyzed 209 49
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentages of subjects
99
(96 to 100)
100
(93 to 100)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection R/JE – Acc, JE – Conv
Comments Non-inferiority of the immune response of JE vaccine (administered concomitantly with Rabies vaccine) accelerated schedule as compared to conventional schedule at 28 day after last active vaccination
Type of Statistical Test Non-Inferiority or Equivalence
Comments The immune response of accelerated schedule of the JE vaccine is considered non-inferior to the conventional schedule if the lower bound of the two-sided 97.5% CI of the difference in the percentages of subjects with PRNT50 titer ≥1:10 measured 28 days after last active vaccination is greater than -10.
Method of Estimation Estimation Parameter Difference in percentages of subjects
Estimated Value -1
Confidence Interval (2-Sided) 97.5%
-4.8 to 7.9
Estimation Comments [Not Specified]
3.Secondary Outcome
Title RVNA Geometric Mean Concentrations (GMCs) At 28 Days After Last Active Vaccination
Hide Description

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.

Time Frame Day 57 (28 days after last active vaccination)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on the PP dataset.
Arm/Group Title R/JE – Conv R – Conv
Hide Arm/Group Description:
Subjects received Rabies and JE vaccines, 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.
Subjects received Rabies vaccine, 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.
Overall Number of Participants Analyzed 157 204
Geometric Mean (95% Confidence Interval)
Unit of Measure: IU/mL
11
(9 to 12)
9.9
(8.57 to 11)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection R/JE – Conv, R – Conv
Comments Non-inferiority of the immune response of Rabies vaccine (administered concomitantly with JE vaccine) as compared to Rabies vaccines (administered alone) as given according to conventional schedule at 28day after last active vaccination
Type of Statistical Test Non-Inferiority or Equivalence
Comments The conventional schedule of Rabies vaccine co-administered with JE vaccine considered non inferior to the conventional schedule of Rabies vaccine administered alone if the lower bound of the two-sided 95% CI of the ratio of GMCs measured 28 days after last active vaccination is greater than 0.667.
Method of Estimation Estimation Parameter Between groups ratio of GMCs
Estimated Value 1.07
Confidence Interval (2-Sided) 95%
0.86 to 1.32
Estimation Comments [Not Specified]
4.Secondary Outcome
Title PRNT50 Geometric Mean Titers (GMTs) At 28 Days After Last Active Vaccination
Hide Description

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.

Time Frame Day 57 (28 days after last active vaccination)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on the PP dataset.
Arm/Group Title R/JE – Conv JE – Conv
Hide Arm/Group Description:
Subjects received Rabies and JE vaccines, 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.
Subjects received JE vaccine, conventional schedule, i.e. 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.
Overall Number of Participants Analyzed 157 49
Geometric Mean (95% Confidence Interval)
Unit of Measure: Titers
291
(256 to 331)
331
(265 to 415)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection R/JE – Conv, JE – Conv
Comments Non-inferiority of the immune response of JE vaccine (administered concomitantly with Rabies vaccine) as compared to JE vaccine (administered alone) as given according to conventional schedule at day 28 after last active vaccination.
Type of Statistical Test Non-Inferiority or Equivalence
Comments The conventional schedule of JE vaccine co-administered with Rabies vaccine considered non inferior to the conventional schedule of JE vaccine administered alone if the lower bound of the two-sided 95% CI of the ratio of GMTs measured 28 days after last active vaccination is greater than 0.5.
Method of Estimation Estimation Parameter Ratio of GMTs
Estimated Value 0.88
Confidence Interval (2-Sided) 95%
0.68 to 1.13
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Percentages of Subjects With RVNA Concentrations ≥0.5 IU/mL At 28 Days After Last Active Vaccination
Hide Description

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.

Time Frame Day 36 and day 57 (28 days after last active vaccination)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on the PP set.
Arm/Group Title R/JE – Acc R – Conv
Hide Arm/Group Description:
Subjects received Rabies and JE vaccines, 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.
Subjects received Rabies vaccine, 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.
Overall Number of Participants Analyzed 206 204
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentages of subjects
99
(96 to 100)
100
(97 to 100)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection R/JE – Acc, R – Conv
Comments Non-inferiority of the Rabies immune response (administered concomitantly with JE vaccine) as given according to an accelerated schedule as compared Rabies vaccine (administered alone) as given to a conventional schedule at day 28 after last active vaccination
Type of Statistical Test Non-Inferiority or Equivalence
Comments The immune response of accelerated schedule of the Rabies vaccine is considered non-inferior to the Rabies vaccine conventional schedule if the lower bound of the two-sided 95% CI of the difference in the percentages of subjects with RVNA titer ≥0.5 IU/mL measured 28 days after last active vaccine administration is greater than -5.
Method of Estimation Estimation Parameter Difference in percentages of subjects
Estimated Value -1
Confidence Interval (2-Sided) 95%
-3.8 to 1.4
Estimation Comments [Not Specified]
6.Secondary Outcome
Title Percentage of Subjects With PRNT50 Titer ≥1:10 At 7 Days After Last Active Vaccination
Hide Description

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.

Time Frame Day 15 and day 36 (28 after last active vaccination)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on the PP dataset.
Arm/Group Title R/JE – Acc JE – Conv
Hide Arm/Group Description:
Subjects received Rabies and JE vaccines, 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.
Group Description Subjects received Rabies and JE vaccines, conventional schedule, i.e. 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.
Overall Number of Participants Analyzed 209 47
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentages of subjects
99
(96 to 100)
100
(92 to 100)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection R/JE – Acc, JE – Conv
Comments Non-inferiority of the immune response of JE vaccine (administered concomitantly with Rabies vaccine) as given according to an accelerated schedule as compared to JE vaccine (administered alone) as given according to a conventional schedule at 7day after last active vaccine administration.
Type of Statistical Test Non-Inferiority or Equivalence
Comments The immune response of accelerated schedule of the JE vaccine considered non-inferior to the conventional schedule if the lower bound of the two-sided 95% CI of the difference in the percentages of subjects with PRNT50 titer ≥1:10 measured 7 days after last active vaccine administration is greater than -10.
Method of Estimation Estimation Parameter Difference in percentages of subjects
Estimated Value -1
Confidence Interval (2-Sided) 95%
-4.1 to 6.2
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Kinetics of Rabies Immune Response Measured as Percentage of Subjects With RVNA Concentration ≥0.5 IU/mL
Hide Description 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.
Time Frame Day 1, 8, 15, 36, 57, 91, 181 and Day 366
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on the PP dataset.
Arm/Group Title R/JE – Conv R/JE – Acc R – Conv
Hide Arm/Group Description:
Subjects received Rabies and JE vaccines, 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.
Subjects received Rabies and JE vaccines, 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.
Subjects received Rabies vaccine, 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.
Overall Number of Participants Analyzed 166 215 218
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentages of subjects
Day 1
1
(0.015 to 3)
1
(0 to 3)
1
(0 to 4)
Day 8 (N=161, 210, 213)
4
(2 to 9)
16
(11 to 21)
4
(2 to 8)
Day 15 (N=161, 209, 210)
99
(96 to 100)
100
(97 to 100)
99
(97 to 100)
Day 36 (N=157, 206, 207)
100
(98 to 100)
99
(96 to 100)
100
(97 to 100)
Day 57 (157, 204, 204)
100
(98 to 100)
97
(93 to 99)
100
(97 to 100)
Day 91 (N=152, 206, 204)
99
(95 to 100)
85
(79 to 90)
98
(95 to 99)
Day 181 (N= 155, 200, 202)
88
(82 to 92)
75
(68 to 81)
89
(84 to 93)
Day 366 (154, 199, 204)
76
(68 to 82)
68
(61 to 74)
80
(74 to 85)
8.Secondary Outcome
Title Kinetics of Rabies Immune Response Measured as the RVNA GMCs
Hide Description 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.
Time Frame Day 1, 8, 15, 36, 57, 91, 181, and 366
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on the PP dataset.
Arm/Group Title R/JE – Conv R/JE – Acc R – Conv
Hide Arm/Group Description:
Subjects received Rabies and JE vaccines, 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.
Subjects received Rabies and JE vaccines, 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.
Subjects received Rabies vaccine, 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.
Overall Number of Participants Analyzed 166 215 218
Geometric Mean (95% Confidence Interval)
Unit of Measure: IU/mL
Day 1
0.052
(0.048 to 0.056)
0.053
(0.049 to 0.056)
0.054
(0.05 to 0.057)
Day 8 (N=161, 210, 213)
0.071
(0.061 to 0.084)
0.13
(0.12 to 0.16)
0.076
(0.066 to 0.088)
Day 15 (N=161, 209, 210),
21
(17 to 25)
26
(22 to 30)
24
(20 to 28)
Day 36 (N=157, 206, 207)
14
(12 to 17)
5.75
(4.95 to 6.67)
13
(11 to 15)
Day 57 (N=157, 204, 204)
10
(8.72 to 12)
3.01
(2.59 to 3.51)
9.66
(8.31 to 11)
Day 91 (N=152, 206, 204)
4.79
(3.98 to 5.76)
1.63
(1.39 to 1.91)
5.04
(4.29 to 5.91)
Day 181 (N= 155, 200, 202)
1.86
(1.15 to 2.3)
1
(0.83 to 1.21)
2.04
(1.69 to 2.46)
Day 366 (N=154, 199, 204)
0.93
(0.75 to 1.16)
0.82
(0.67 to 1)
1.14
(0.94 to 1.38)
9.Secondary Outcome
Title Kinetics of JE Immune Response Measured as Percentage of Subjects With PRNT50 Titers ≥1:10
Hide Description 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).
Time Frame Days 1, 15, 22, 36, 57, 91, 181 and 366
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on the PP dataset.
Arm/Group Title R/JE – Conv R/JE – Acc JE – Conv
Hide Arm/Group Description:
Subjects received Rabies and JE vaccines, 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.
Subjects received Rabies and JE vaccines, 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.
Subjects received JE vaccine, 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.
Overall Number of Participants Analyzed 165 215 55
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: Percentages of subjects
Day 1
1
(0 to 4)
6
(3 to 10)
9
(3 to 20)
Day 15 (N=0, 209, 0)
NA [1] 
(NA to NA)
99
(96 to 100)
NA [1] 
(NA to NA)
Day 22 (N=0, 208, 0)
NA [1] 
(NA to NA)
100
(97 to 100)
NA [1] 
(NA to NA)
Day 36 (157, 206, 47)
99
(97 to 100)
99
(96 to 100)
100
(92 to 100)
Day 57 (N=157, 204, 49)
100
(98 to 100)
98
(95 to 99)
100
(93 to 100)
Day 91 (N=0, 206, 0)
NA [1] 
(NA to NA)
98
(95 to 99)
NA [1] 
(NA to NA)
Day 181 (N=155, 200, 49)
94
(88 to 97)
98
(94 to 99)
92
(80 to 98)
Day 366 (N=154, 199, 48)
86
(79 to 91)
94
(90 to 97)
88
(75 to 95)
[1]
Analysis was not performed in this group at this timepoint.
10.Secondary Outcome
Title Kinetics of JE Immune Response Measured as PRNT50 GMTs
Hide Description 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).
Time Frame Day 1, 15, 22, 36, 57, 91, 181, and 366 (accelerated schedule) and day 1, 36, 57, 181, and 366 (conventional schedule)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on the PP dataset.
Arm/Group Title R/JE – Conv R/JE – Acc JE – Conv
Hide Arm/Group Description:
Subjects received Rabies and JE vaccines, 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.
Subjects received Rabies and JE vaccines, 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.
Subjects received JE vaccine, 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.
Overall Number of Participants Analyzed 165 215 55
Geometric Mean (95% Confidence Interval)
Unit of Measure: Titers
Day 1
5.13
(4.84 to 5.43)
5.63
(5.35 to 5.92)
5.73
(5.2 to 6.33)
Day 15 (N=0, 209, 0)
NA [1] 
(NA to NA)
715
(608 to 842)
NA [1] 
(NA to NA)
Day 22 (0, 208, 0)
NA [1] 
(NA to NA)
1255
(1068 to 1475)
NA [1] 
(NA to NA)
Day 36 (N=157, 206, 47)
292
(247 to 346)
690
(595 to 801)
376
(277 to 510)
Day 57 (N= 157, 204, 49)
299
(254 to 352)
372
(322 to 430)
337
(252 to 451)
Day 91 (N=0, 206, 0)
NA [1] 
(NA to NA)
228
(192 to 272)
NA [1] 
(NA to NA)
Day 181 (N=155, 200, 49)
63
(53 to 75)
151
(130 to 176)
64
(47 to 87)
Day 366 (N=154, 199, 48)
39
(33 to 47)
117
(100 to 137)
39
(28 to 54)
[1]
Analysis was not performed in this group at this timepoint.
11.Secondary Outcome
Title Number of Subjects Who Reported Solicited Local Adverse Events After Each Rabies Vaccination
Hide Description 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).
Time Frame Day 1 through day 7 after each vaccination (on day 1, 4, 8 and 29)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on the solicited safety set, i.e. the subjects in the exposed population who provided postvaccination solicited safety data.
Arm/Group Title R/JE – Conv R/JE – Acc R – Conv
Hide Arm/Group Description:
Subjects received Rabies and JE vaccines, 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.
Subjects received Rabies and JE vaccines, 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.
Subjects received Rabies vaccine, 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.
Overall Number of Participants Analyzed 166 217 220
Measure Type: Number
Unit of Measure: Number of subjects
Erythema (day 1 to 7) 13 31 28
Induration (day 1 to 7) 3 16 11
Pain (day 1 to 7) 43 69 72
Erythema (day 4 to 10) NA [1]  17 NA [1] 
Induration (day 4 to 10) NA [1]  9 NA [1] 
Pain (day 4 to 10) NA [1]  55 NA [1] 
Erythema (day 8 to 14) 8 31 29
Induration (day 8 to 14) 10 15 17
Pain (day 8 to 14) 57 87 90
Erythema (day 29 to 35) 23 NA [2]  45
Induration (day 29 to 35) 18 NA [2]  32
Pain (day 29 to 35) 52 NA [2]  87
[1]
Subjects in this group received placebo at day 4
[2]
Subjects in this group received placebo at day 29
12.Secondary Outcome
Title Number of Subjects Who Reported Solicited Local AEs After Each JE Vaccination
Hide Description 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).
Time Frame Day 1 through day 7 after each vaccination (on day 1, 8 and 29)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on the solicited safety set.
Arm/Group Title R/JE – Conv R/JE – Acc JE – Conv
Hide Arm/Group Description:
Subjects received Rabies and JE vaccines, 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.
Subjects received Rabies and JE vaccines, 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.
Subjects received JE vaccine, 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.
Overall Number of Participants Analyzed 166 217 56
Measure Type: Number
Unit of Measure: Number of subjects
Erythema (day 1 to 7) 20 30 6
Induration (day 1 to 7) 13 19 5
Pain (day 1 to 7) 82 102 26
Erythema (day 8 to 14) NA [1]  18 NA [1] 
Induration (day 8 to 14) NA [1]  12 NA [1] 
Pain (day 8 to 14) NA [1]  60 NA [1] 
Erythema (day 29 to 35) 12 NA [2]  5
Induration (day 29 to 35) 5 NA [2]  4
Pain (day 29 to 35) 46 NA [2]  12
[1]
Subjects in this group didn't receive JE vaccination on day 8.
[2]
Subjects in this group didn't receive JE vaccination on day 29.
13.Secondary Outcome
Title Number of Subjects Who Reported Solicited Local AEs After Each Placebo Injection
Hide Description 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).
Time Frame Day 1 through day 7 after each injection (day 1, 4, 8 and 29)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on the solicited safety set.
Arm/Group Title R/JE – Conv R/JE – Acc R – Conv JE – Conv
Hide Arm/Group Description:
Subjects received Rabies and JE vaccines, 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.
Subjects received Rabies and JE vaccines, 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.
Subjects received Rabies vaccine, 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.
Subjects received JE vaccine, 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.
Overall Number of Participants Analyzed 163 213 220 56
Measure Type: Number
Unit of Measure: Number of Subjects
Erythema (day 1 to 7) NA [1]  NA [1]  20 3
Induration (day 1 to 7) NA [1]  NA [1]  4 5
Pain (day 1 to 7) NA [1]  NA [1]  26 7
Erythema (day 4 to 10) 8 NA [2]  13 3
Induration (day 4 to 10) 1 NA [2]  4 2
Pain (day 4 to 10) 7 NA [2]  15 3
Erythema (day 8 to 14) 1 NA [3]  11 4
Erythema (day 8 to 14 after 2nd Placebo dose) NA [4]  NA [3]  NA [4]  3
Induration (day 8 to 14) 0 NA [3]  5 1
Induration (day 8 to 14 after 2nd Placebo dose) NA [4]  NA [3]  NA [4]  1
Pain (day 8 to 14) 19 NA [3]  20 3
Pain (day 8 to 14 after 2nd Placebo dose) NA [4]  NA [3]  NA [4]  5
Erythema (day 29 to 35) NA [5]  15 15 3
Erythema (day 29 to 35 after 2nd Placebo dose) NA [5]  14 NA [6]  NA [6] 
Induration (day 29 to 35) NA [5]  6 4 1
Induration (day 29 to 35 after 2nd Placebo dose) NA [5]  4 NA [6]  NA [6] 
Pain (day 29 to 35) NA [5]  15 28 3
Pain (day 29 to 35 after 2nd Placebo dose) NA [5]  19 NA [6]  NA [6] 
[1]
Subjects in this group didn't receive placebo at day 1.
[2]
Subjects in this group didn't receive placebo at day 4.
[3]
Subjects in this group didn't receive placebo at day 8.
[4]
Subjects in this group received only 1 dose of placebo at day 8.
[5]
Subjects in this group didn't receive placebo at day 29.
[6]
Subjects in this group received only 1 dose of placebo at day 29.
14.Secondary Outcome
Title Number of Subjects Who Reported Solicited Systemic AEs and Other Indicators of Reactogenicity After Each Vaccination
Hide Description 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.
Time Frame Day 1 through day 7 after each vaccination (day 1, 4, 8 and 29)
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on the solicited safety set.
Arm/Group Title R/JE – Conv R/JE – Acc R – Conv JE – Conv
Hide Arm/Group Description:
Subjects received Rabies and JE vaccines, 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.
Subjects received Rabies and JE vaccines, 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.
Subjects received Rabies vaccine, 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.
Subjects received JE vaccine, 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.
Overall Number of Participants Analyzed 166 217 220 56
Measure Type: Number
Unit of Measure: Number of Subjects
Fatigue (day 1 to 7) 39 56 46 16
Headache (day 1 to 7) 35 46 38 14
Myalgia (day 1 to 7) 27 55 31 7
Arthralgia (day 1 to 7) 8 13 7 1
Loss of Appetite (day1 to day 7) 10 8 12 6
Nausea (day1 to day 7) 8 7 13 4
Body temperature (≥38 °C, day 1 to day 7) 1 2 2 0
Analgesic/Antipyretic used (day 1 to day 7) 11 11 8 3
Fatigue (day 4 to 10) 14 30 33 5
Headache (day 4 to 10) 17 28 29 3
Myalgia (day 4 to 10) 11 19 14 1
Arthralgia (day 4 to 10) 1 9 9 0
Loss of Appetite (day4 to day 10) 4 8 9 2
Nausea (day4 to day 10) 4 5 8 0
Body temperature (≥38 °C, day 4 to day 10) 1 1 2 0
Analgesic/Antipyretic used (day 4 to 10) 8 10 15 2
Fatigue (day 8 to 14) 24 47 47 6
Headache (day 8 to 14) 33 43 41 3
Myalgia (day 8 to 14) 22 41 38 1
Arthralgia (day 8 to 14) 6 9 13 1
Loss of Appetite (day8 to day 14) 10 14 13 2
Nausea (day8 to day 14) 5 14 16 2
Body temperature (≥38 °C, day 8 to 14) 2 1 5 0
Analgesic/Antipyretic used (day 8 to 14) 10 17 20 2
Fatigue (day 29 to 35) 21 29 36 3
Headache (day 29 to 35) 27 22 40 4
Myalgia (day 29 to 35) 23 15 28 2
Arthralgia (day 29 to 35) 5 6 14 1
Body temperature (≥38 °C, day 29 to day 35) 1 2 1 0
Analgesic/Antipyretic used (day 29 to day 35) 9 10 11 3
Loss if appetite (day 29 to day 25) 2 8 9 2
nausea (day29 to day 25) 7 12 9 2
15.Secondary Outcome
Title Numbers of Subjects Reporting Unsolicited AEs After Any Vaccination From Day 1 Through Day 57
Hide Description Safety was assessed as the number of subjects who reported unsolicited AEs after any vaccination given according to accelerated and conventional schedule.
Time Frame Day 1 through Day 57
Hide Outcome Measure Data
Hide Analysis Population Description
Analysis was done on the unsolicited safety set, ie, the subjects in the exposed population who provided postvaccination unsolicited safety data.
Arm/Group Title R/JE – Conv R/JE – Acc R – Conv JE – Conv
Hide Arm/Group Description:
Subjects received Rabies and JE vaccines, conventional schedule, i.e. 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.
Subjects received Rabies and JE vaccines, accelerated schedule, i.e. 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.
Subjects received Rabies vaccine, conventional schedule, i.e. 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.
Subjects received JE vaccine, conventional schedule, i.e. 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.
Overall Number of Participants Analyzed 166 217 220 56
Measure Type: Number
Unit of Measure: Number of subjects
Any AE 69 108 110 29
SAEs 2 3 2 3
AEs leading to premature withdrawal 1 0 0 1
Time Frame Solicited AEs were collected for 7 days after each vaccination. All unsolicited AEs, serious adverse events (SAEs), AEs leading to study and/or treatment withdrawal were collected through day 57. From day 57 to day 366 vaccine-related SAEs were collected.
Adverse Event Reporting Description Solicited adverse events were collected by systematic assessment, unsolicited AEs by non-systematic assessment. SAEs analysis was done one the unsolicited safety set, other AEs analysis was done on the overall safety set.
 
Arm/Group Title R/JE – Conv R/JE – Acc R – Conv JE – Conv
Hide Arm/Group Description Subjects received Rabies and JE vaccines, conventional schedule, i.e. 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. Subjects received Rabies and JE vaccines, accelerated schedule, i.e. 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. Subjects received Rabies vaccine, conventional schedule, i.e. 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. Subjects received JE vaccine, conventional schedule, i.e. 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.
All-Cause Mortality
R/JE – Conv R/JE – Acc R – Conv JE – Conv
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
R/JE – Conv R/JE – Acc R – Conv JE – Conv
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/166 (1.20%)   3/217 (1.38%)   2/220 (0.91%)   3/56 (5.36%) 
Cardiac disorders         
ATRIAL FIBRILLATION  1  0/166 (0.00%)  0/217 (0.00%)  1/220 (0.45%)  0/56 (0.00%) 
TACHYCARDIA  1  0/166 (0.00%)  0/217 (0.00%)  1/220 (0.45%)  0/56 (0.00%) 
Eye disorders         
EYELID OEDEMA  1  0/166 (0.00%)  0/217 (0.00%)  0/220 (0.00%)  1/56 (1.79%) 
Gastrointestinal disorders         
PANCREATITIS ACUTE  1  0/166 (0.00%)  1/217 (0.46%)  0/220 (0.00%)  0/56 (0.00%) 
Hepatobiliary disorders         
CHOLECYSTITIS  1  0/166 (0.00%)  0/217 (0.00%)  0/220 (0.00%)  1/56 (1.79%) 
CHOLELITHIASIS  1  0/166 (0.00%)  0/217 (0.00%)  0/220 (0.00%)  1/56 (1.79%) 
Injury, poisoning and procedural complications         
HUMERUS FRACTURE  1  1/166 (0.60%)  0/217 (0.00%)  0/220 (0.00%)  0/56 (0.00%) 
MENISCUS INJURY  1  0/166 (0.00%)  1/217 (0.46%)  0/220 (0.00%)  0/56 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)         
OVARIAN GERM CELL TERATOMA BENIGN  1  0/166 (0.00%)  1/217 (0.46%)  0/220 (0.00%)  0/56 (0.00%) 
Nervous system disorders         
SYNCOPE  1  0/166 (0.00%)  0/217 (0.00%)  1/220 (0.45%)  0/56 (0.00%) 
Psychiatric disorders         
ALCOHOL WITHDRAWAL SYNDROME  1  0/166 (0.00%)  0/217 (0.00%)  0/220 (0.00%)  1/56 (1.79%) 
DEPRESSION  1  1/166 (0.60%)  0/217 (0.00%)  0/220 (0.00%)  0/56 (0.00%) 
Skin and subcutaneous tissue disorders         
PRURITUS GENERALISED  1  0/166 (0.00%)  0/217 (0.00%)  0/220 (0.00%)  1/56 (1.79%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (17.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
R/JE – Conv R/JE – Acc R – Conv JE – Conv
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   138/166 (83.13%)   186/217 (85.71%)   185/220 (84.09%)   45/56 (80.36%) 
Gastrointestinal disorders         
NAUSEA  1  19/166 (11.45%)  31/217 (14.29%)  35/220 (15.91%)  9/56 (16.07%) 
General disorders         
FATIGUE  1  54/166 (32.53%)  93/217 (42.86%)  84/220 (38.18%)  19/56 (33.93%) 
INJECTION SITE ERYTHEMA  1  48/166 (28.92%)  73/217 (33.64%)  85/220 (38.64%)  13/56 (23.21%) 
INJECTION SITE INDURATION  1  29/166 (17.47%)  43/217 (19.82%)  48/220 (21.82%)  10/56 (17.86%) 
INJECTION SITE PAIN  1  115/166 (69.28%)  146/217 (67.28%)  131/220 (59.55%)  31/56 (55.36%) 
Infections and infestations         
NASOPHARYNGITIS * 1  22/166 (13.25%)  33/217 (15.21%)  32/220 (14.55%)  7/56 (12.50%) 
Metabolism and nutrition disorders         
DECREASED APPETITE  1  19/166 (11.45%)  24/217 (11.06%)  27/220 (12.27%)  9/56 (16.07%) 
Musculoskeletal and connective tissue disorders         
ARTHRALGIA  1  13/166 (7.83%)  29/217 (13.36%)  31/220 (14.09%)  3/56 (5.36%) 
MYALGIA  1  50/166 (30.12%)  75/217 (34.56%)  60/220 (27.27%)  10/56 (17.86%) 
Nervous system disorders         
HEADACHE  1  63/166 (37.95%)  94/217 (43.32%)  95/220 (43.18%)  19/56 (33.93%) 
Indicates events were collected by systematic assessment
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (17.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Name/Title: Posting Director
Organization: Novartis Vaccines
Responsible Party: Novartis ( Novartis Vaccines )
ClinicalTrials.gov Identifier: NCT01662440     History of Changes
Other Study ID Numbers: V49_23
2011-005173-23 ( EudraCT Number )
First Submitted: August 2, 2012
First Posted: August 10, 2012
Results First Submitted: October 6, 2014
Results First Posted: December 8, 2014
Last Update Posted: December 8, 2014