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Immunogenicity and Safety of Tetravalent Dengue Vaccine (TDV) at the End of Shelf Life in Healthy Adults

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03771963
Recruitment Status : Completed
First Posted : December 11, 2018
Results First Posted : June 7, 2021
Last Update Posted : June 7, 2021
Sponsor:
Information provided by (Responsible Party):
Takeda

Study Type Interventional
Study Design Allocation: N/A;   Intervention Model: Single Group Assignment;   Masking: None (Open Label);   Primary Purpose: Prevention
Condition Dengue Fever
Intervention Biological: Tetravalent Dengue Vaccine (TDV)
Enrollment 200
Recruitment Details Participants took part in the study at 2 investigative sites in the United States from 28 March 2019 to 13 March 2020.
Pre-assignment Details Healthy participants were enrolled in this study to receive Tetravalent Dengue Vaccine (TDV) on Days 1 and 90.
Arm/Group Title Tetravalent Dengue Vaccine (TDV)
Hide Arm/Group Description TDV 0.5 mL, injection, subcutaneously (SC), once on Day 1 (first dose) and Day 90 (second dose).
Period Title: Overall Study
Started 200
Completed 168
Not Completed 32
Reason Not Completed
Lost to Follow-up             22
Withdrawal of Consent             10
Arm/Group Title Tetravalent Dengue Vaccine (TDV)
Hide Arm/Group Description TDV 0.5 mL, injection, subcutaneously (SC), once on Day 1 (first dose) and Day 90 (second dose).
Overall Number of Baseline Participants 200
Hide Baseline Analysis Population Description
Safety Set included all participants who received at least 1 dose of TDV trial vaccine.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 200 participants
40.27  (12.035)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 200 participants
Female
101
  50.5%
Male
99
  49.5%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 200 participants
Hispanic or Latino
64
  32.0%
Not Hispanic or Latino
136
  68.0%
Unknown or Not Reported
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 200 participants
American Indian or Alaska Native
0
   0.0%
Asian
5
   2.5%
Native Hawaiian or Other Pacific Islander
1
   0.5%
Black or African American
41
  20.5%
White
148
  74.0%
More than one race
3
   1.5%
Unknown or Not Reported
2
   1.0%
Region of Enrollment  
Measure Type: Count of Participants
Unit of measure:  Participants
United States Number Analyzed 200 participants
200
 100.0%
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 200 participants
170.72  (9.330)
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 200 participants
80.23  (15.220)
Body Mass Index (BMI)   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 200 participants
27.45  (4.248)
[1]
Measure Description: BMI= weight (kg)/[height (m)^2]
1.Primary Outcome
Title Geometric Mean Titers (GMT) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Day 120
Hide Description GMTs of neutralizing antibodies for each of the 4 dengue serotypes were measured by microneutralization test 50% [MNT50]. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3, and DENV-4.
Time Frame One month post second dose (Day 120)
Hide Outcome Measure Data
Hide Analysis Population Description
Per-protocol Set (PPS) excludes all participants seropositive for dengue virus at Baseline and includes all participants in the Full Analysis Set (FAS- who received at least 1 dose of trial vaccine with valid pre-dose and post-dose measurement for immunogenicity assessment) who have no major protocol violations, with data available for analysis.
Arm/Group Title Tetravalent Dengue Vaccine (TDV)
Hide Arm/Group Description:
TDV 0.5 mL, injection, subcutaneously (SC), once on Day 1 (first dose) and Day 90 (second dose).
Overall Number of Participants Analyzed 132
Geometric Mean (95% Confidence Interval)
Unit of Measure: titer
DENV-1
557.4
(417.0 to 744.9)
DENV-2
2047.4
(1739.7 to 2409.5)
DENV-3
131.8
(105.0 to 165.4)
DENV-4
119.6
(97.7 to 146.5)
2.Secondary Outcome
Title Seropositivity Rates for Each of the 4 Dengue Serotypes at Days 120 and 270
Hide Description Seropositivity rate was defined as the percentage of participants being seropositive, derived from titers of dengue-neutralizing antibodies. Seropositivity was defined as a reciprocal neutralizing titer ≥10 (for each serotype). Seropositivity rates were assessed for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4.
Time Frame One month and six months post second dose (Days 120 and 270)
Hide Outcome Measure Data
Hide Analysis Population Description
The PPS excludes all participants seropositive for dengue virus at Baseline and includes all participants in the FAS who have no major protocol violations. Number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Tetravalent Dengue Vaccine (TDV)
Hide Arm/Group Description:
TDV 0.5 mL, injection, subcutaneously (SC), once on Day 1 (first dose) and Day 90 (second dose).
Overall Number of Participants Analyzed 139
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Day 120: DENV-1 Number Analyzed 132 participants
99.2
(95.9 to 100.0)
Day 120: DENV-2 Number Analyzed 132 participants
100.0
(97.2 to 100.0)
Day 120: DENV-3 Number Analyzed 132 participants
97.7
(93.5 to 99.5)
Day 120: DENV-4 Number Analyzed 132 participants
99.2
(95.9 to 100.0)
Day 270: DENV-1 Number Analyzed 133 participants
97.0
(92.5 to 99.2)
Day 270: DENV-2 Number Analyzed 133 participants
98.5
(94.7 to 99.8)
Day 270: DENV-3 Number Analyzed 133 participants
85.7
(78.6 to 91.2)
Day 270: DENV-4 Number Analyzed 133 participants
86.5
(79.5 to 91.8)
3.Secondary Outcome
Title Seropositivity Rates for Multiple (2, 3, or 4) Dengue Serotypes at Days 120 and 270
Hide Description Seropositivity rate was defined as the percentage of participants being seropositive, derived from titers of dengue-neutralizing antibodies. Seropositivity was defined as a reciprocal neutralizing titer ≥10. The dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity for multiple dengue serotypes was summarized in the following categories: tetravalent and at least trivalent.
Time Frame One month and six months post second dose (Days 120 and 270)
Hide Outcome Measure Data
Hide Analysis Population Description
The PPS excludes all participants seropositive for dengue virus at Baseline and includes all participants in the FAS who have no major protocol violations. Number analyzed is the number of participants with data available for analysis at the given time point.
Arm/Group Title Tetravalent Dengue Vaccine (TDV)
Hide Arm/Group Description:
TDV 0.5 mL, injection, subcutaneously (SC), once on Day 1 (first dose) and Day 90 (second dose).
Overall Number of Participants Analyzed 139
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
Day 120: At Least Trivalent Number Analyzed 132 participants
99.2
(95.9 to 100.0)
Day 120: Tetravalent Number Analyzed 132 participants
97.0
(92.4 to 99.2)
Day 270: At Least Trivalent Number Analyzed 133 participants
91.0
(84.8 to 95.3)
Day 270: Tetravalent Number Analyzed 133 participants
78.9
(71.0 to 85.5)
4.Secondary Outcome
Title Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Day 270
Hide Description GMTs of neutralizing antibodies were assessed for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.
Time Frame Six months post second dose (Day 270)
Hide Outcome Measure Data
Hide Analysis Population Description
PPS excludes all participants seropositive for dengue virus at Baseline and includes all participants in the FAS who have no major protocol violations, with data available for analysis.
Arm/Group Title Tetravalent Dengue Vaccine (TDV)
Hide Arm/Group Description:
TDV 0.5 mL, injection, subcutaneously (SC), once on Day 1 (first dose) and Day 90 (second dose).
Overall Number of Participants Analyzed 133
Geometric Mean (95% Confidence Interval)
Unit of Measure: titer
DENV-1
311.6
(222.8 to 435.9)
DENV-2
1170.6
(953.9 to 1436.5)
DENV-3
63.0
(48.4 to 82.0)
DENV-4
57.6
(44.2 to 75.0)
5.Secondary Outcome
Title Percentage of Participants With Solicited Local (Injection Site) Reactions Following Each Vaccination by Severity
Hide Description Solicited local adverse events (AEs) [at injection site] were collected by participants using diary cards within 7 days after each vaccination and included injection site pain [Grade 0 (no pain), 1 (mild: no interference with daily activity), 2 (moderate: interference with daily activity with or without treatment) and 3 (severe: prevents daily activity with or without treatment)], injection site erythema [Grade 0 (<25 mm), 1 (25 - ≤ 50 mm), 2 (>50 - ≤ 100 mm), 3 (> 100 mm)] and injection site swelling [Grade 0 (<25 mm), 1 (25 - ≤ 50 mm), 2 (>50 - ≤ 100 mm), 3 (> 100 mm)]. The percentages were rounded off to the first decimal place. Only categories with at least 1 participant are reported.
Time Frame Up to 7 days (Day of vaccination + 6 subsequent days) after each of the vaccination
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Set included all participants who received at least 1 dose of TDV trial vaccine. Number analyzed is the number of participants with data available for the specific category.
Arm/Group Title Tetravalent Dengue Vaccine (TDV)
Hide Arm/Group Description:
TDV 0.5 mL, injection, subcutaneously (SC), once on Day 1 (first dose) and Day 90 (second dose).
Overall Number of Participants Analyzed 200
Measure Type: Number
Unit of Measure: percentage of participants
After First Vaccination, Any Solicited Local AEs Number Analyzed 192 participants
35.9
After First Vaccination, Pain: Any Severity Number Analyzed 192 participants
29.7
After First Vaccination, Pain: Mild Number Analyzed 192 participants
25.5
After First Vaccination, Pain: Moderate Number Analyzed 192 participants
3.6
After First Vaccination, Pain: Severe Number Analyzed 192 participants
0.5
After First Vaccination, Erythema: Any Severity Number Analyzed 192 participants
13.0
After First Vaccination, Erythema: Mild Number Analyzed 192 participants
12.0
After First Vaccination, Erythema: Moderate Number Analyzed 192 participants
1.0
After First Vaccination, Swelling: Any Severity Number Analyzed 192 participants
4.2
After First Vaccination, Swelling: Mild Number Analyzed 192 participants
4.2
After Second Vaccination, Any Solicited Local AEs Number Analyzed 167 participants
32.3
After Second Vaccination, Pain: Any Severity Number Analyzed 167 participants
31.1
After Second Vaccination, Pain: Mild Number Analyzed 167 participants
27.5
After Second Vaccination, Pain: Moderate Number Analyzed 167 participants
2.4
After Second Vaccination, Pain: Severe Number Analyzed 167 participants
1.2
After Second Vaccination, Erythema: Any Severity Number Analyzed 167 participants
6.0
After Second Vaccination, Erythema: Mild Number Analyzed 167 participants
6.0
After Second Vaccination, Swelling: Any Severity Number Analyzed 167 participants
2.4
After Second Vaccination, Swelling: Mild Number Analyzed 167 participants
2.4
6.Secondary Outcome
Title Percentage of Participants With Solicited Systemic Adverse Events Following Each Vaccination by Severity
Hide Description Solicited systemic AEs were collected by participants using diary cards within 14 days after each vaccination and included fever, headache, asthenia, malaise and myalgia. Severity grades were: Grade 0: none, Grade 1: mild (no interference with daily activity), Grade 2: moderate (interference with daily activity with or without treatment), Grade 3: severe (prevents normal daily activity with or without treatment). Fever is defined as body temperature greater than or equal to 38°C (100.4°F). Fever was excluded from the overall count as no severity grading was applied for it. The percentages were rounded off to the first decimal place. Only categories with at least 1 participant are reported.
Time Frame Up to 14 days (Day of vaccination + 13 subsequent days) after each vaccination
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Set included all participants who received at least 1 dose of TDV trial vaccine. Number analyzed is the number of participants with data available for the specific category.
Arm/Group Title Tetravalent Dengue Vaccine (TDV)
Hide Arm/Group Description:
TDV 0.5 mL, injection, subcutaneously (SC), once on Day 1 (first dose) and Day 90 (second dose).
Overall Number of Participants Analyzed 200
Measure Type: Number
Unit of Measure: percentage of participants
After First Vaccination, Any Solicited Systemic Local AEs Number Analyzed 192 participants
42.2
After First Vaccination, Headache: Any Severity Number Analyzed 192 participants
30.2
After First Vaccination, Headache: Mild Number Analyzed 192 participants
22.9
After First Vaccination, Headache: Moderate Number Analyzed 192 participants
5.7
After First Vaccination, Headache: Severe Number Analyzed 192 participants
1.6
After First Vaccination, Myalgia: Any Severity Number Analyzed 192 participants
25.5
After First Vaccination, Myalgia: Mild Number Analyzed 192 participants
20.8
After First Vaccination, Myalgia: Moderate Number Analyzed 192 participants
3.1
After First Vaccination, Myalgia: Severe Number Analyzed 192 participants
1.6
After First Vaccination, Asthenia: Any Severity Number Analyzed 192 participants
16.7
After First Vaccination, Asthenia: Mild Number Analyzed 192 participants
10.4
After First Vaccination, Asthenia: Moderate Number Analyzed 192 participants
5.2
After First Vaccination, Asthenia: Severe Number Analyzed 192 participants
1.0
After First Vaccination, Malaise: Any Severity Number Analyzed 192 participants
19.8
After First Vaccination, Malaise: Mild Number Analyzed 192 participants
13.0
After First Vaccination, Malaise: Moderate Number Analyzed 192 participants
4.7
After First Vaccination, Malaise: Severe Number Analyzed 192 participants
2.1
After First Vaccination, Fever: Any Number Analyzed 189 participants
2.6
After First Vaccination, Fever: 38.0-<38.5 Number Analyzed 189 participants
2.1
After First Vaccination, Fever: 38.5-<39.0 Number Analyzed 189 participants
0.5
After Second Vaccination, Any Solicited Systemic Local AEs Number Analyzed 167 participants
34.1
After Second Vaccination, Headache: Any Severity Number Analyzed 167 participants
22.8
After Second Vaccination, Headache: Mild Number Analyzed 167 participants
16.2
After Second Vaccination, Headache: Moderate Number Analyzed 167 participants
5.4
After Second Vaccination, Headache: Severe Number Analyzed 167 participants
1.2
After Second Vaccination, Myalgia: Any Severity Number Analyzed 167 participants
22.2
After Second Vaccination, Myalgia: Mild Number Analyzed 167 participants
20.4
After Second Vaccination, Myalgia: Moderate Number Analyzed 167 participants
1.2
After Second Vaccination, Myalgia: Severe Number Analyzed 167 participants
0.6
After Second Vaccination, Asthenia: Any Severity Number Analyzed 167 participants
12.0
After Second Vaccination, Asthenia: Mild Number Analyzed 167 participants
7.8
After Second Vaccination, Asthenia: Moderate Number Analyzed 167 participants
3.0
After Second Vaccination, Asthenia: Severe Number Analyzed 167 participants
1.2
After Second Vaccination, Malaise: Any Severity Number Analyzed 167 participants
13.2
After Second Vaccination, Malaise: Mild Number Analyzed 167 participants
9.0
After Second Vaccination, Malaise: Moderate Number Analyzed 167 participants
3.0
After Second Vaccination, Malaise: Severe Number Analyzed 167 participants
1.2
After Second Vaccination, Fever: Any Number Analyzed 166 participants
1.2
After Second Vaccination, Fever: 38.0-<38.5 Number Analyzed 166 participants
0.6
After Second Vaccination, Fever: 38.5-<39.0 Number Analyzed 166 participants
0.6
7.Secondary Outcome
Title Percentage of Participants With Any Unsolicited Adverse Events Following Each Vaccination
Hide Description An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a study vaccine; it does not necessarily have to have a causal relationship with study vaccine administration.
Time Frame Up to 28 days after each vaccination (Day of vaccination + 27 subsequent days)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Set included all participants who received at least 1 dose of TDV trial vaccine. Number analyzed is the number of participants with data available for the specific category.
Arm/Group Title Tetravalent Dengue Vaccine (TDV)
Hide Arm/Group Description:
TDV 0.5 mL, injection, subcutaneously (SC), once on Day 1 (first dose) and Day 90 (second dose).
Overall Number of Participants Analyzed 200
Measure Type: Number
Unit of Measure: percentage of participants
After First Vaccination Number Analyzed 200 participants
11.5
After Second Vaccination Number Analyzed 176 participants
10.8
8.Secondary Outcome
Title Percentage of Participants With Serious Adverse Events (SAEs)
Hide Description An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, leads to a congenital anomaly / birth defect in the offspring of a participant, or is an important medical event which may require intervention to prevent the items listed above or may expose the participant to danger, even though the event is not immediately life threatening or fatal or does not result in hospitalization.
Time Frame From first vaccination (Day 1) through end of study (Day 270)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Set included all participants who received at least 1 dose of TDV trial vaccine.
Arm/Group Title Tetravalent Dengue Vaccine (TDV)
Hide Arm/Group Description:
TDV 0.5 mL, injection, subcutaneously (SC), once on Day 1 (first dose) and Day 90 (second dose).
Overall Number of Participants Analyzed 200
Measure Type: Number
Unit of Measure: percentage of participants
2.5
9.Secondary Outcome
Title Percentage of Participants With Medically Attended Adverse Events (MAAEs)
Hide Description MAAEs are defined as AEs leading to an unscheduled visit to or by a healthcare professional, including visits to an emergency department, but not fulfilling seriousness criteria.
Time Frame From first vaccination (Day 1) through end of study (Day 270)
Hide Outcome Measure Data
Hide Analysis Population Description
Safety Set included all participants who received at least 1 dose of TDV trial vaccine.
Arm/Group Title Tetravalent Dengue Vaccine (TDV)
Hide Arm/Group Description:
TDV 0.5 mL, injection, subcutaneously (SC), once on Day 1 (first dose) and Day 90 (second dose).
Overall Number of Participants Analyzed 200
Measure Type: Number
Unit of Measure: percentage of participants
26.0
Time Frame All-cause mortality and Serious adverse events: From first vaccination (Day 1) through end of study (Day 270). Other (Non-serious) adverse events: Up to 28 days after each vaccination (Day of vaccination + 27 subsequent days).
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 treatment.
 
Arm/Group Title Tetravalent Dengue Vaccine (TDV)
Hide Arm/Group Description TDV 0.5 mL, injection, subcutaneously (SC), once on Day 1 (first dose) and Day 90 (second dose).
All-Cause Mortality
Tetravalent Dengue Vaccine (TDV)
Affected / at Risk (%)
Total   0/200 (0.00%) 
Hide Serious Adverse Events
Tetravalent Dengue Vaccine (TDV)
Affected / at Risk (%)
Total   5/200 (2.50%) 
Cardiac disorders   
Bradycardia † 1  1/200 (0.50%) 
Gastrointestinal disorders   
Inguinal hernia † 1  1/200 (0.50%) 
Hepatobiliary disorders   
Hepatic failure † 1  1/200 (0.50%) 
Infections and infestations   
Sepsis † 1  1/200 (0.50%) 
Musculoskeletal and connective tissue disorders   
Osteoarthritis † 1  1/200 (0.50%) 
1
Term from vocabulary, MedDRA 23.0
†
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Tetravalent Dengue Vaccine (TDV)
Affected / at Risk (%)
Total   0/200 (0.00%) 
[Not Specified]
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: Study Director
Organization: Takeda
Phone: +1-877-825-3327
EMail: TrialDisclosures@takeda.com
Layout table for additonal information
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT03771963    
Other Study ID Numbers: DEN-307
U1111-1222-2812 ( Registry Identifier: WHO )
First Submitted: December 10, 2018
First Posted: December 11, 2018
Results First Submitted: May 11, 2021
Results First Posted: June 7, 2021
Last Update Posted: June 7, 2021