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Safety and Immunogenicity of Three Formulations of Takeda's Tetravalent Dengue Vaccine Candidate (TDV)

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ClinicalTrials.gov Identifier: NCT02193087
Recruitment Status : Completed
First Posted : July 17, 2014
Results First Posted : June 29, 2016
Last Update Posted : July 18, 2019
Sponsor:
Information provided by (Responsible Party):
Takeda

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Basic Science
Condition Dengue Fever
Interventions Drug: TDV Liquid Formulation 1
Drug: TDV Liquid Formulation 2
Drug: TDV IDT Lyophilized
Drug: Placebo
Enrollment 1002
Recruitment Details Participants took part in the study at 7 investigative sites in the United States from 22 July 2014 to 19 May 2015.
Pre-assignment Details Healthy volunteers were enrolled in a 2:1:1:6 ratio into 1 of 4 study groups: 1 study group received 1 dose and 3 study groups received 2 doses.
Arm/Group Title Group A: TDV Liquid + Placebo Group B: TDV Liquid Group C: TDV Liquid Group D: TDV Lyophilized
Hide Arm/Group Description Takeda's Tetravalent Dengue Vaccine Candidate (TDV) Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1, and TDV Liquid Formulation placebo-matching solution, subcutaneous injection, once on Day 90 (Month 3). TDV Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1 and Day 90 (Month 3). TDV Liquid Formulation 2, subcutaneous injection on Day 1 and Day 90 (Month 3). TDV Lyophilized Formulation reconstituted with water, subcutaneous injection on Day 1 and Day 90 (Month 3).
Period Title: Overall Study
Started 199 100 100 603
Received Vaccination 197 97 100 602
Completed 162 86 93 524
Not Completed 37 14 7 79
Reason Not Completed
Adverse Event             2             0             0             11
Lost to Follow-up             14             6             4             37
Protocol Violation             2             0             1             2
Withdrawal by Subject             10             3             1             19
Other Reason Not Specified             7             2             1             9
Did Not Receive Any Vaccination             2             3             0             1
Arm/Group Title Group A: TDV Liquid + Placebo Group B: TDV Liquid Group C: TDV Liquid Group D: TDV Lyophilized Total
Hide Arm/Group Description Takeda's Tetravalent Dengue Vaccine Candidate (TDV) Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1, and TDV Liquid Formulation placebo-matching solution, subcutaneous injection, once on Day 90 (Month 3). TDV Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1 and Day 90 (Month 3). TDV Liquid Formulation 2, subcutaneous injection on Day 1 and Day 90 (Month 3). TDV Lyophilized Formulation reconstituted with water, subcutaneous injection on Day 1 and Day 90 (Month 3). Total of all reporting groups
Overall Number of Baseline Participants 199 100 100 603 1002
Hide Baseline Analysis Population Description
All randomized participants.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 199 participants 100 participants 100 participants 603 participants 1002 participants
32.1  (8.66) 30.9  (8.72) 34.1  (9.20) 31.9  (8.89) 32.1  (8.88)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Adults (18-64 Years) Number Analyzed 199 participants 100 participants 100 participants 603 participants 1002 participants
199 100 100 603 1002
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 199 participants 100 participants 100 participants 603 participants 1002 participants
Female
109
  54.8%
51
  51.0%
47
  47.0%
298
  49.4%
505
  50.4%
Male
90
  45.2%
49
  49.0%
53
  53.0%
305
  50.6%
497
  49.6%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 199 participants 100 participants 100 participants 603 participants 1002 participants
Hispanic or Latino 40 22 21 120 203
Non-Hispanic or Latino 152 75 76 464 767
Not Reported 7 3 3 15 28
Unknown 0 0 0 3 3
Missing 0 0 0 1 1
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 199 participants 100 participants 100 participants 603 participants 1002 participants
American Indian or Alaska Native 4 2 1 8 15
Asian 5 1 3 16 25
Black or African American 51 27 26 146 250
Native Hawaiian or Other Pacific Islander 2 0 1 2 5
White 125 66 69 408 668
Multiracial 3 1 0 15 19
Missing 9 3 0 8 20
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 199 participants 100 participants 100 participants 603 participants 1002 participants
199 100 100 603 1002
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 199 participants 100 participants 100 participants 603 participants 1002 participants
169.55  (9.284) 171.13  (10.466) 169.84  (9.727) 170.69  (9.680) 170.42  (9.689)
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 199 participants 100 participants 100 participants 603 participants 1002 participants
76.95  (14.362) 78.96  (16.878) 75.96  (16.099) 77.49  (15.649) 77.37  (15.569)
Body Mass Index (BMI)  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 199 participants 100 participants 100 participants 603 participants 1002 participants
26.71  (4.180) 26.81  (4.496) 26.30  (5.006) 26.53  (4.513) 26.57  (4.494)
1.Primary Outcome
Title Geometric Mean Titer (GMT) of Neutralizing Antibodies for Each of the Four Dengue Serotypes Comparing Group D To Groups A and B Combined
Hide Description

Geometric mean titer (GMT) of neutralizing antibodies for each of the four dengue serotypes as measured by Plaque Reduction Neutralization Test resulting in 50% reduction in Plaques (PRNT50). The four dengue serotypes are DEN-1, DEN-2, DEN-3 and DEN-4.

A 90% Confidence Interval (CI) for the ratio of GMT (or equivalently the difference of the log transformed GMT) was provided, for each serotype, for the comparison of the lyophilized formulation (Group D) versus the liquid formulation 1 (Groups A+B combined). An Analysis of Variance (ANOVA) model for the natural log-transformed GMT at month 1 with study group as a factor was used for analysis.

Time Frame Month 1
Hide Outcome Measure Data
Hide Analysis Population Description
Per-Protocol Set (PPS) included all randomized participants who received the planned number of investigational vaccine doses, had serology data at Baseline and Month 1 and had no major protocol violations. Participants seropositive at Baseline are not included.
Arm/Group Title Group A + Group B Combined Group D: TDV Lyophilized
Hide Arm/Group Description:

Group A: Takeda's Tetravalent Dengue Vaccine Candidate (TDV) Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1, and TDV Liquid Formulation placebo-matching solution, subcutaneous injection, once on Day 90 (Month 3).

Group B: TDV Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1 and Day 90 (Month 3).

TDV Lyophilized Formulation reconstituted with water, subcutaneous injection on Day 1 and Day 90 (Month 3).
Overall Number of Participants Analyzed 220 454
Least Squares Mean (90% Confidence Interval)
Unit of Measure: titer
DEN-1
635.04
(530.62 to 760.00)
181.23
(159.92 to 205.37)
DEN-2
15104.68
(13135.48 to 17369.09)
16072.59
(14583.29 to 17713.99)
DEN-3
186.32
(151.11 to 229.74)
272.75
(235.75 to 315.57)
DEN-4
88.87
(72.29 to 109.25)
65.67
(56.88 to 75.82)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Group A + Group B Combined, Group D: TDV Lyophilized
Comments DEN-1
Type of Statistical Test Non-Inferiority or Equivalence
Comments Based on the Two One-Sided Tests (TOST) with α=0.05, if the 90% CI for the ratio of GMT for a given dengue serotype for the comparison was within the range of 0.67 and 1, then the 2 formulations were deemed equivalent.
Method of Estimation Estimation Parameter LS Mean Ratio
Estimated Value 0.29
Confidence Interval (2-Sided) 90%
0.23 to 0.36
Estimation Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Group A + Group B Combined, Group D: TDV Lyophilized
Comments DEN-2
Type of Statistical Test Non-Inferiority or Equivalence
Comments Based on the Two One-Sided Tests (TOST) with α=0.05, if the 90% CI for the ratio of GMT for a given dengue serotype for the comparison was within the range of 0.67 and 1, then the 2 formulations were deemed equivalent.
Method of Estimation Estimation Parameter LS Mean Ratio
Estimated Value 1.06
Confidence Interval (2-Sided) 90%
0.90 to 1.26
Estimation Comments [Not Specified]
Show Statistical Analysis 3 Hide Statistical Analysis 3
Statistical Analysis Overview Comparison Group Selection Group A + Group B Combined, Group D: TDV Lyophilized
Comments DEN-3
Type of Statistical Test Non-Inferiority or Equivalence
Comments Based on the Two One-Sided Tests (TOST) with α=0.05, if the 90% CI for the ratio of GMT for a given dengue serotype for the comparison was within the range of 0.67 and 1, then the 2 formulations were deemed equivalent.
Method of Estimation Estimation Parameter LS Mean Ratio
Estimated Value 1.46
Confidence Interval (2-Sided) 90%
1.13 to 1.89
Estimation Comments [Not Specified]
Show Statistical Analysis 4 Hide Statistical Analysis 4
Statistical Analysis Overview Comparison Group Selection Group A + Group B Combined, Group D: TDV Lyophilized
Comments DEN-4
Type of Statistical Test Non-Inferiority or Equivalence
Comments Based on the Two One-Sided Tests (TOST) with α=0.05, if the 90% CI for the ratio of GMT for a given dengue serotype for the comparison was within the range of 0.67 and 1, then the 2 formulations were deemed equivalent.
Method of Estimation Estimation Parameter LS Mean Ratio
Estimated Value 0.74
Confidence Interval (2-Sided) 90%
0.57 to 0.95
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Geometric Mean Titers (GMT) of Neutralizing Antibodies for Each of the Four Dengue Serotypes Comparing Group D With Group B
Hide Description Geometric mean titer (GMT) of neutralizing antibodies for each of the four dengue serotypes as measured by Plaque Reduction Neutralization Test resulting in 50% reduction in Plaques (PRNT50). The four dengue serotypes are DEN-1, DEN-2, DEN-3 and DEN-4. ANOVA model for the natural log-transformed GMT at month 1 with study group as a factor was used for analysis.
Time Frame Months 1 and 4
Hide Outcome Measure Data
Hide Analysis Population Description
PPS included all randomized participants who received the planned number of investigational vaccine doses, had serology data at Baseline and Month 1 and had no major protocol violations. Participants seropositive at Baseline are not included. "n" in each of the categories is the number of participants with data available at the given time-point.
Arm/Group Title Group B: TDV Liquid Group D: TDV Lyophilized
Hide Arm/Group Description:
TDV Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1 and Day 90 (Month 3).
TDV Lyophilized Formulation reconstituted with water, subcutaneous injection on Day 1 and Day 90 (Month 3).
Overall Number of Participants Analyzed 74 454
Least Squares Mean (90% Confidence Interval)
Unit of Measure: titer
Month 1 DEN-1 (n=74, 454)
627.56
(458.91 to 858.18)
181.23
(159.71 to 205.63)
Month 1 DEN-2 (n=74, 454)
17876.66
(14186.79 to 22526.23)
16072.59
(14640.33 to 17644.97)
Month 1 DEN-3 (n=74, 454)
220.29
(154.23 to 314.64)
272.75
(236.19 to 314.98)
Month 1 DEN-4 (n=74, 454)
88.25
(62.10 to 125.43)
65.67
(56.98 to 75.68)
Month 4 DEN-1 (n=73, 435)
267.80
(205.46 to 349.06)
113.43
(101.76 to 126.44)
Month 4 DEN-2 (n=73, 435)
4160.29
(3508.92 to 4932.58)
3772.95
(3518.74 to 4045.53)
Month 4 DEN-3 (n=73, 435)
106.98
(85.08 to 134.52)
132.73
(120.84 to 145.79)
Month 4 DEN-4 (n=73, 435)
31.56
(24.82 to 40.14)
28.84
(26.13 to 31.82)
3.Secondary Outcome
Title Percentage of Participants With a Seropositive Response for Each of the Four Dengue Serotypes Comparing Group D With Groups A and B Combined
Hide Description A seropositive response is defined as a reciprocal neutralizing titer ≥ 10. The four dengue serotypes are DEN-1, DEN-2, DEN-3 and DEN-4.
Time Frame Month 1
Hide Outcome Measure Data
Hide Analysis Population Description
Per-Protocol Set (PPS) included all randomized participants who received the planned number of investigational vaccine doses, had serology data at Baseline and Month 1, and have no major protocol violations. Participants seropositive at Baseline are not included.
Arm/Group Title Group A + Group B Combined Group D: TDV Lyophilized
Hide Arm/Group Description:

Group A: TDV Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1, and TDV Liquid Formulation placebo-matching solution, subcutaneous injection, once on Day 90 (Month 3).

Group B: TDV Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1 and Day 90 (Month 3).

TDV Lyophilized Formulation reconstituted with water, subcutaneous injection on Day 1 and Day 90 (Month 3).
Overall Number of Participants Analyzed 220 454
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
DEN-1
97.7
(94.8 to 99.3)
93.6
(91.0 to 95.7)
DEN-2
100.0
(98.3 to 100.0)
99.6
(98.4 to 99.9)
DEN-3
91.8
(87.4 to 95.1)
93.4
(90.7 to 95.5)
DEN-4
80.9
(75.1 to 85.9)
80.0
(76.0 to 83.5)
4.Secondary Outcome
Title Percentage of Participants With a Seropositive Response for Each of the Four Dengue Serotypes Comparing Group D With Group B
Hide Description A seropositive response is defined as a reciprocal neutralizing titer ≥ 10. The four dengue serotypes are DEN-1, DEN-2, DEN-3 and DEN-4.
Time Frame Months 1 and 4
Hide Outcome Measure Data
Hide Analysis Population Description
PPS included all randomized participants who received the planned number of investigational vaccine doses, had serology data at Baseline and Month 1 and had no major protocol violations. Participants seropositive at Baseline are not included. “n” in each of the categories is the number of participants with data available at the given time-point.
Arm/Group Title Group B: TDV Liquid Group D: TDV Lyophilized
Hide Arm/Group Description:
TDV Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1 and Day 90 (Month 3).
TDV Lyophilized Formulation reconstituted with water, subcutaneous injection on Day 1 and Day 90 (Month 3).
Overall Number of Participants Analyzed 74 454
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Month 1 DEN-1 (n=74, 454)
97.3
(90.6 to 99.7)
93.6
(91.0 to 95.7)
Month 1 DEN-2 (n=74, 454)
100.0
(95.1 to 100.0)
99.6
(98.4 to 99.9)
Month 1 DEN-3 (n=74, 454)
95.9
(88.6 to 99.2)
93.4
(90.7 to 95.5)
Month 1 DEN-4 (n=74, 454)
78.4
(67.3 to 87.1)
80.0
(76.0 to 83.5)
Month 4 DEN-1 (n=73, 435)
97.3
(90.5 to 99.7)
98.2
(96.4 to 99.2)
Month 4 DEN-2 (n=73, 435)
100.0
(95.0 to 100.0)
100.0
(99.1 to 100.0)
Month 4 DEN-3 (n=73, 435)
98.6
(92.6 to 100.0)
98.9
(97.3 to 99.6)
Month 4 DEN-4 (n=73, 435)
83.6
(73.0 to 91.2)
79.3
(75.2 to 83.0)
5.Secondary Outcome
Title Percentage of Participants With Solicited Local (Injection Site) Adverse Events (AEs)
Hide Description Solicited local AEs at injection site are defined as pain, erythema and swelling that occurred at least once within 7 days after either vaccination, as recorded by the participants in a diary. Percentages are based on the number of participants with diary data available.
Time Frame Days 1 through 7 after each vaccination
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the Safety Set (SS) with evaluable data and who received at least 1 dose of study vaccine (or placebo), including a partial dose. “n” in each of the categories is the number of participants with data available for analysis.
Arm/Group Title Group A: TDV Liquid + Placebo Group B: TDV Liquid Group A and Group B Combined Group C: TDV Liquid Group D: TDV Lyophilized
Hide Arm/Group Description:
Takeda's Tetravalent Dengue Vaccine Candidate (TDV) Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1, and TDV Liquid Formulation placebo-matching solution, subcutaneous injection, once on Day 90 (Month 3).
TDV Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1 and Day 90 (Month 3).

Group A: Takeda's Tetravalent Dengue Vaccine Candidate (TDV) Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1, and TDV Liquid Formulation placebo-matching solution, subcutaneous injection, once on Day 90 (Month 3).

Group B: TDV Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1 and Day 90 (Month 3).

TDV Liquid Formulation 2, subcutaneous injection on Day 1 and Day 90 (Month 3).
TDV Lyophilized Formulation reconstituted with water, subcutaneous injection on Day 1 and Day 90 (Month 3).
Overall Number of Participants Analyzed 191 95 294 99 583
Measure Type: Number
Unit of Measure: percentage of participants
Pain (n=191, 95, 99, 583) 43.5 48.4 45.1 51.5 45.3
Erythema (n=191, 95, 99, 582) 35.6 41.1 37.4 51.5 43.0
Swelling (n=191, 95, 99, 582) 11.5 20.0 14.3 24.2 21.6
6.Secondary Outcome
Title Percentage of Participants With Solicited Systemic Adverse Events (AEs)
Hide Description Solicited systemic AEs are defined as asthenia, fever, headache, malaise, and myalgia that occurred at least once within 14 days after either vaccination, as recorded by the participants in a diary. Percentages are based on the number of participants with diary data available.
Time Frame Days 1 through 14 after each vaccination
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the SS with evaluable data and who received at least 1 dose of study vaccine (or placebo), including a partial dose.
Arm/Group Title Group A: TDV Liquid + Placebo Group B: TDV Liquid Group C: TDV Liquid Group D: TDV Lyophilized
Hide Arm/Group Description:
Takeda's Tetravalent Dengue Vaccine Candidate (TDV) Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1, and TDV Liquid Formulation placebo-matching solution, subcutaneous injection, once on Day 90 (Month 3).
TDV Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1 and Day 90 (Month 3).
TDV Liquid Formulation 2, subcutaneous injection on Day 1 and Day 90 (Month 3).
TDV Lyophilized Formulation reconstituted with water, subcutaneous injection on Day 1 and Day 90 (Month 3).
Overall Number of Participants Analyzed 191 95 99 584
Measure Type: Number
Unit of Measure: percentage of participants
Headache 40.8 43.2 38.4 41.1
Asthenia 27.7 23.2 25.3 26.9
Malaise 29.3 27.4 25.3 25.3
Myalgia 30.4 38.9 30.3 33.2
Fever (≥38 °C) 1.6 3.2 1.0 1.7
7.Secondary Outcome
Title Percentage of Participants With Solicited Local (Injection Site) Adverse Events (AEs) by Severity
Hide Description The percentage of participants with solicited local AEs at injection site of varying severity are reported. Solicited local AEs are defined as pain, erythema and swelling that occurred at least once within 7 days after either vaccination, as recorded by the participants in a diary. Participants with multiple episodes are categorized using the highest severity level. Percentages are based on the number of participants with diary data available.
Time Frame Days 1 through 7 after each vaccination
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the SS with evaluable data and who received at least 1 dose of study vaccine (or placebo), including a partial dose. “n” in each of the categories is the number of participants with data available for analysis.
Arm/Group Title Group A: TDV Liquid + Placebo Group B: TDV Liquid Group C: TDV Liquid Group D: TDV Lyophilized
Hide Arm/Group Description:
Takeda's Tetravalent Dengue Vaccine Candidate (TDV) Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1, and TDV Liquid Formulation placebo-matching solution, subcutaneous injection, once on Day 90 (Month 3).
TDV Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1 and Day 90 (Month 3).
TDV Liquid Formulation 2, subcutaneous injection on Day 1 and Day 90 (Month 3).
TDV Lyophilized Formulation reconstituted with water, subcutaneous injection on Day 1 and Day 90 (Month 3).
Overall Number of Participants Analyzed 191 95 99 583
Measure Type: Number
Unit of Measure: percentage of participants
Pain_Mild (n=191, 95, 99, 583) 34.6 36.8 41.4 34.8
Pain_Moderate (n=191, 95, 99, 583) 6.8 8.4 8.1 9.3
Pain_Severe (n=191, 95, 99, 583) 2.1 3.2 2.0 1.2
Erythema_Mild (n=191, 95, 99, 582) 18.3 22.1 18.2 16.0
Erythema_Moderate (n=191, 95, 99, 582) 2.1 9.5 11.1 6.4
Erythema_Severe (n=191, 95, 99, 582) 0 0 0 0.2
Swelling_Mild (n=191, 95, 99, 582) 1.6 5.3 9.1 5.0
Swelling_Moderate (n=191, 95, 99, 582) 0 3.2 5.1 1.4
Swelling_Severe (n=191, 95, 99, 582) 0 0 0 0.2
8.Secondary Outcome
Title Percentage of Participants With Solicited Systemic Adverse Events (AEs) by Severity
Hide Description The percentage of participants with solicited systemic AEs of varying severity are reported. Solicited systemic AEs are defined as asthenia, fever, headache, malaise, and myalgia that occurred at least once within 14 days after either vaccination, as recorded by the participants in a diary. Participants with multiple episodes are categorized using the highest severity level. Percentages are based on the number of participants with diary data available.
Time Frame Days 1 through 14 after each vaccination
Hide Outcome Measure Data
Hide Analysis Population Description
Participants from the SS with evaluable data and who received at least 1 dose of study vaccine (or placebo), including a partial dose.
Arm/Group Title Group A: TDV Liquid + Placebo Group B: TDV Liquid Group C: TDV Liquid Group D: TDV Lyophilized
Hide Arm/Group Description:
Takeda's Tetravalent Dengue Vaccine Candidate (TDV) Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1, and TDV Liquid Formulation placebo-matching solution, subcutaneous injection, once on Day 90 (Month 3).
TDV Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1 and Day 90 (Month 3).
TDV Liquid Formulation 2, subcutaneous injection on Day 1 and Day 90 (Month 3).
TDV Lyophilized Formulation reconstituted with water, subcutaneous injection on Day 1 and Day 90 (Month 3).
Overall Number of Participants Analyzed 191 95 99 584
Measure Type: Number
Unit of Measure: percentage of participants
Headache_Mild 27.2 26.3 21.2 23.1
Headache_Moderate 8.4 9.5 13.1 13.5
Headache_Severe 5.2 7.4 4.0 4.5
Asthenia_Mild 18.8 11.6 13.1 16.4
Asthenia_Moderate 5.8 10.5 10.1 7.9
Asthenia_Severe 3.1 1.1 2.0 2.6
Malaise_Mild 17.8 15.8 15.2 14.0
Malaise_Moderate 7.3 9.5 7.1 8.7
Malaise_Severe 4.2 2.1 3.0 2.6
Myalgia_Mild 20.9 23.2 22.2 23.5
Myalgia_Moderate 7.3 11.6 6.1 8.4
Myalgia_Severe 2.1 4.2 2.0 1.4
Fever_38.0 - 38.4 °C 1.0 2.1 1.0 1.0
Fever_38.5 - 38.9 °C 0.5 1.1 0 0.7
Fever_39.0 - 40.0 °C 0 0 0 0
Fever_>40 °C 0 0 0 0
9.Secondary Outcome
Title Percentage of Participants With Any Unsolicited Adverse Events (AEs)
Hide Description Unsolicited AEs are any AEs that are not solicited local or systemic AEs, as defined by this study, that occurred at least once within 28 days after either vaccination. An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. The investigator assessed whether the AE was related to the study vaccination.
Time Frame Up to Day 28 after each vaccination
Hide Outcome Measure Data
Hide Analysis Population Description
SS included all randomized participants who received at least 1 dose of study vaccine (or placebo), including a partial dose.
Arm/Group Title Group A: TDV Liquid + Placebo Group B: TDV Liquid Group C: TDV Liquid Group D: TDV Lyophilized
Hide Arm/Group Description:
Takeda's Tetravalent Dengue Vaccine Candidate (TDV) Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1, and TDV Liquid Formulation placebo-matching solution, subcutaneous injection, once on Day 90 (Month 3).
TDV Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1 and Day 90 (Month 3).
TDV Liquid Formulation 2, subcutaneous injection on Day 1 and Day 90 (Month 3).
TDV Lyophilized Formulation reconstituted with water, subcutaneous injection on Day 1 and Day 90 (Month 3).
Overall Number of Participants Analyzed 197 97 100 602
Measure Type: Number
Unit of Measure: percentage of participants
40.1 47.4 45.0 43.7
10.Secondary Outcome
Title Percentage of Participants With Serious Adverse Events (SAEs)
Hide Description A serious adverse event (SAE) is defined as any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, is a congenital anomaly / birth defect or is medically important due to other reasons than the above mentioned criteria.
Time Frame Up to 6 Months after the last dose (9 months)
Hide Outcome Measure Data
Hide Analysis Population Description
SS included all randomized participants who received at least 1 dose of study vaccine (or placebo), including a partial dose.
Arm/Group Title Group A: TDV Liquid + Placebo Group B: TDV Liquid Group C: TDV Liquid Group D: TDV Lyophilized
Hide Arm/Group Description:
Takeda's Tetravalent Dengue Vaccine Candidate (TDV) Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1, and TDV Liquid Formulation placebo-matching solution, subcutaneous injection, once on Day 90 (Month 3).
TDV Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1 and Day 90 (Month 3).
TDV Liquid Formulation 2, subcutaneous injection on Day 1 and Day 90 (Month 3).
TDV Lyophilized Formulation reconstituted with water, subcutaneous injection on Day 1 and Day 90 (Month 3).
Overall Number of Participants Analyzed 197 97 100 602
Measure Type: Number
Unit of Measure: percentage of participants
1.0 1.0 0 1.3
11.Secondary Outcome
Title Percentage of Participants With Markedly Abnormal Laboratory Values in the Safety Sub-Set
Hide Description Percentage of participants with markedly abnormal standard safety laboratory values collected at any time after the first vaccination.
Time Frame Days 8, 15, 91, 97 and 104
Hide Outcome Measure Data
Hide Analysis Population Description
The Safety Laboratory Sub-Set included randomly chosen participants from each treatment group for whom samples for clinical safety lab tests were collected and who received at least one vaccination dose. "n" in each of the categories is the number of participants with data available at the given time-point.
Arm/Group Title Group A: TDV Liquid + Placebo Group B: TDV Liquid Group C: TDV Liquid Group D: TDV Lyophilized
Hide Arm/Group Description:
Takeda's Tetravalent Dengue Vaccine Candidate (TDV) Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1, and TDV Liquid Formulation placebo-matching solution, subcutaneous injection, once on Day 90 (Month 3).
TDV Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1 and Day 90 (Month 3).
TDV Liquid Formulation 2, subcutaneous injection on Day 1 and Day 90 (Month 3).
TDV Lyophilized Formulation reconstituted with water, subcutaneous injection on Day 1 and Day 90 (Month 3).
Overall Number of Participants Analyzed 121 61 64 405
Measure Type: Number
Unit of Measure: percentage of participants
Hemoglobin 0 0 0 0.2
Neutrophils (Abs.) 2.5 0 0 0.5
Lymphocytes (Abs.) 0.8 0 0 0.5
Eosinophils (Abs.) 0.8 1.6 0 0
Neutrophils (%) 0.8 0 0 0.2
Lymphocytes (%) 0 0 0 0.5
Eosinophils (%) 2.5 1.6 0 0.5
Platelet Count 0 0 0 0.2
Prothrombin Time 0 0 0 0.7
aPTT 0 0 0 0.5
ALT(SGPT) (n=121,61,64,404) 3.3 0 3.1 1.7
AST(SGOT) (n=121,61,64,404) 2.5 0 1.6 1.5
Alkaline Phosphatase (n=121,61,64,404) 0.8 0 0 0.2
BUN (n=121,61,64,404) 0 0 0 0.2
Time Frame Serious Adverse Events: 9 months. Non-Serious Adverse Events: 28 Days after each vaccination.
Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study vaccine.
 
Arm/Group Title Group A: TDV Liquid + Placebo Group B: TDV Liquid Group C: TDV Liquid Group D: TDV Lyophilized
Hide Arm/Group Description Takeda's Tetravalent Dengue Vaccine Candidate (TDV) Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1, and TDV Liquid Formulation placebo-matching solution, subcutaneous injection, once on Day 90 (Month 3). TDV Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1 and Day 90 (Month 3). TDV Liquid Formulation 2, subcutaneous injection on Day 1 and Day 90 (Month 3). TDV Lyophilized Formulation reconstituted with water, subcutaneous injection on Day 1 and Day 90 (Month 3).
All-Cause Mortality
Group A: TDV Liquid + Placebo Group B: TDV Liquid Group C: TDV Liquid Group D: TDV Lyophilized
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Group A: TDV Liquid + Placebo Group B: TDV Liquid Group C: TDV Liquid Group D: TDV Lyophilized
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   2/197 (1.02%)   1/97 (1.03%)   0/100 (0.00%)   8/602 (1.33%) 
Hepatobiliary disorders         
Cholecystitis  1  0/197 (0.00%)  1/97 (1.03%)  0/100 (0.00%)  0/602 (0.00%) 
Infections and infestations         
Gastroenteritis  1  0/197 (0.00%)  0/97 (0.00%)  0/100 (0.00%)  1/602 (0.17%) 
Hepatitis C  1  1/197 (0.51%)  0/97 (0.00%)  0/100 (0.00%)  0/602 (0.00%) 
Injury, poisoning and procedural complications         
Heat exhaustion  1  0/197 (0.00%)  0/97 (0.00%)  0/100 (0.00%)  1/602 (0.17%) 
Injury  1  0/197 (0.00%)  0/97 (0.00%)  0/100 (0.00%)  1/602 (0.17%) 
Nervous system disorders         
Altered state of consciousness  1  0/197 (0.00%)  0/97 (0.00%)  0/100 (0.00%)  1/602 (0.17%) 
Cerebral artery occlusion  1  0/197 (0.00%)  0/97 (0.00%)  0/100 (0.00%)  1/602 (0.17%) 
Complex partial seizures  1  0/197 (0.00%)  0/97 (0.00%)  0/100 (0.00%)  1/602 (0.17%) 
Guillain-Barre syndrome  1  0/197 (0.00%)  0/97 (0.00%)  0/100 (0.00%)  1/602 (0.17%) 
Lacunar infarction  1  0/197 (0.00%)  0/97 (0.00%)  0/100 (0.00%)  1/602 (0.17%) 
Temporal lobe epilepsy  1  0/197 (0.00%)  0/97 (0.00%)  0/100 (0.00%)  1/602 (0.17%) 
Psychiatric disorders         
Major depression  1  1/197 (0.51%)  0/97 (0.00%)  0/100 (0.00%)  0/602 (0.00%) 
Reproductive system and breast disorders         
Cervical cyst  1  0/197 (0.00%)  0/97 (0.00%)  0/100 (0.00%)  1/602 (0.17%) 
Ovarian cyst  1  0/197 (0.00%)  0/97 (0.00%)  0/100 (0.00%)  1/602 (0.17%) 
Respiratory, thoracic and mediastinal disorders         
Pneumothorax  1  0/197 (0.00%)  0/97 (0.00%)  0/100 (0.00%)  1/602 (0.17%) 
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 2%
Group A: TDV Liquid + Placebo Group B: TDV Liquid Group C: TDV Liquid Group D: TDV Lyophilized
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   50/197 (25.38%)   34/97 (35.05%)   29/100 (29.00%)   178/602 (29.57%) 
Blood and lymphatic system disorders         
Lymphadenopathy  1  1/197 (0.51%)  2/97 (2.06%)  0/100 (0.00%)  5/602 (0.83%) 
Gastrointestinal disorders         
Nausea  1  4/197 (2.03%)  2/97 (2.06%)  0/100 (0.00%)  21/602 (3.49%) 
Diarrhoea  1  0/197 (0.00%)  2/97 (2.06%)  1/100 (1.00%)  10/602 (1.66%) 
Vomiting  1  4/197 (2.03%)  2/97 (2.06%)  0/100 (0.00%)  11/602 (1.83%) 
General disorders         
Injection site erythema  1  10/197 (5.08%)  6/97 (6.19%)  10/100 (10.00%)  41/602 (6.81%) 
Injection site pain  1  5/197 (2.54%)  6/97 (6.19%)  2/100 (2.00%)  25/602 (4.15%) 
Injection site pruritus  1  5/197 (2.54%)  4/97 (4.12%)  7/100 (7.00%)  19/602 (3.16%) 
Fatigue  1  1/197 (0.51%)  2/97 (2.06%)  0/100 (0.00%)  8/602 (1.33%) 
Injection site discolouration  1  1/197 (0.51%)  1/97 (1.03%)  3/100 (3.00%)  11/602 (1.83%) 
Injection site swelling  1  0/197 (0.00%)  2/97 (2.06%)  1/100 (1.00%)  8/602 (1.33%) 
Infections and infestations         
Gastroenteritis  1  1/197 (0.51%)  4/97 (4.12%)  0/100 (0.00%)  5/602 (0.83%) 
Upper respiratory tract infection  1  10/197 (5.08%)  3/97 (3.09%)  2/100 (2.00%)  23/602 (3.82%) 
Nasopharyngitis  1  3/197 (1.52%)  0/97 (0.00%)  3/100 (3.00%)  9/602 (1.50%) 
Injury, poisoning and procedural complications         
Laceration  1  0/197 (0.00%)  2/97 (2.06%)  0/100 (0.00%)  2/602 (0.33%) 
Contusion  1  1/197 (0.51%)  2/97 (2.06%)  0/100 (0.00%)  2/602 (0.33%) 
Musculoskeletal and connective tissue disorders         
Arthralgia  1  1/197 (0.51%)  2/97 (2.06%)  2/100 (2.00%)  6/602 (1.00%) 
Back pain  1  1/197 (0.51%)  1/97 (1.03%)  3/100 (3.00%)  7/602 (1.16%) 
Myalgia  1  1/197 (0.51%)  3/97 (3.09%)  0/100 (0.00%)  6/602 (1.00%) 
Neck pain  1  4/197 (2.03%)  1/97 (1.03%)  1/100 (1.00%)  3/602 (0.50%) 
Nervous system disorders         
Headache  1  8/197 (4.06%)  3/97 (3.09%)  0/100 (0.00%)  22/602 (3.65%) 
Respiratory, thoracic and mediastinal disorders         
Nasal congestion  1  2/197 (1.02%)  4/97 (4.12%)  0/100 (0.00%)  6/602 (1.00%) 
Cough  1  0/197 (0.00%)  2/97 (2.06%)  0/100 (0.00%)  7/602 (1.16%) 
Oropharyngeal pain  1  3/197 (1.52%)  2/97 (2.06%)  1/100 (1.00%)  8/602 (1.33%) 
Skin and subcutaneous tissue disorders         
Pruritus  1  2/197 (1.02%)  2/97 (2.06%)  1/100 (1.00%)  5/602 (0.83%) 
Indicates events were collected by 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.
The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Medical Director Clinical Science, Study Official
Organization: Takeda
Phone: +1-877-825-3327
EMail: trialdisclosures@takeda.com
Layout table for additonal information
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT02193087     History of Changes
Other Study ID Numbers: DEN-106
U1111-1154-9746 ( Other Identifier: World Health Organization )
First Submitted: July 15, 2014
First Posted: July 17, 2014
Results First Submitted: May 19, 2016
Results First Posted: June 29, 2016
Last Update Posted: July 18, 2019