Clinical Trial Results:
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Investigate the Immunogenicity and Safety of Subcutaneous Administration of a Tetravalent Dengue Vaccine Candidate in Healthy Adolescent Subjects in Non-Endemic Area(s) for Dengue
Summary
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EudraCT number |
2018-003980-77 |
Trial protocol |
Outside EU/EEA |
Global end of trial date |
26 Jan 2019
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Results information
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Results version number |
v1(current) |
This version publication date |
02 Apr 2020
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First version publication date |
02 Apr 2020
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Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
DEN-315
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03341637 | ||
WHO universal trial number (UTN) |
U1111-1192-7827 | ||
Sponsors
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Sponsor organisation name |
Takeda Vaccines, Inc.
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Sponsor organisation address |
40 Landsdowne Street, Cambridge, United States, MA 02139
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Public contact |
Medical Director, Takeda Vaccines, Inc., +1 8778253327, trialdisclosures@takeda.com
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Scientific contact |
Medical Director, Takeda Vaccines, Inc., +1 8778253327, trialdisclosures@takeda.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-001888-PIP01-15 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
26 Jan 2019
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
26 Jan 2019
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main objective of this study was to describe the neutralizing antibody response against each dengue serotype at 1 month post second dose of TDV or placebo in dengue-naive adolescent participants.
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Protection of trial subjects |
All study participants were required to read and sign an Informed Consent Form.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
14 Dec 2017
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Mexico: 400
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Worldwide total number of subjects |
400
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EEA total number of subjects |
0
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
400
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Participants took part in the study at 5 investigative sites in Mexico from 14-Dec-2017 to 26-Jan-2019. | |||||||||||||||||||||
Pre-assignment
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Screening details |
Healthy volunteers were enrolled in a 3:1 ratio into 2 parallel study groups: 1 study group received 2 doses of Tetravalent Dengue vaccine (TDV) and another group received 2 doses of TDV matching placebo subcutaneously (SC). | |||||||||||||||||||||
Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | |||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | |||||||||||||||||||||
Arm description |
TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo- matching TDV injection
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Normal Saline (0.9% NaCl) subcutaneous injection
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Arm title
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Tetravalent Dengue Vaccine (TDV) | |||||||||||||||||||||
Arm description |
TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
TDV injection
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
TDV subcutaneous injection
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tetravalent Dengue Vaccine (TDV)
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Reporting group description |
TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). | ||
Reporting group title |
Tetravalent Dengue Vaccine (TDV)
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Reporting group description |
TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). |
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End point title |
Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Day 120 [1] | ||||||||||||||||||||||||
End point description |
GMTs of neutralizing antibodies were measured by microneutralization test 50% [MNT50] for each of the 4 Dengue Serotypes. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity is defined as reciprocal neutralizing titer ≥10. Per Protocol Set (PPS): all participants seronegative to all serotypes of dengue virus at baseline who received at least 1 dose of trial vaccine, who had a valid pre-dose (baseline) and at least 1 valid post-dose measurement for immunogenicity and no major protocol violations. n=participants with data available at given time-point.
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End point type |
Primary
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End point timeframe |
One month post second dose (Day 120)
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Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analyses was not available. |
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No statistical analyses for this end point |
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End point title |
Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Day 270 | ||||||||||||||||||||||||
End point description |
GMTs of neutralizing antibodies were measured by microneutralization test 50% [MNT50] for each of the 4 Dengue Serotypes. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity is defined as reciprocal neutralizing titer ≥10. PPS: all participants seronegative to all serotypes of dengue virus at baseline who received at least 1 dose of trial vaccine, who had a valid pre-dose (baseline) and at least 1 valid post-dose measurement for immunogenicity and no major protocol violations. n=participants with data available at given time-point. 99999 indicates data for 95% CI was not evaluable at this time point.
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End point type |
Secondary
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End point timeframe |
Six months post second dose (Day 270)
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No statistical analyses for this end point |
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End point title |
Seropositivity Rates for Each of the 4 Dengue Serotypes | ||||||||||||||||||||||||||||||||||||
End point description |
Seropositivity rate, defined as the percentage of participants seropositive, was derived from the titers of dengue-neutralizing antibodies. Seropositivity defined as a reciprocal neutralizing titer ≥10. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4. PPS: all participants seronegative to all serotypes of dengue virus at baseline who received at least 1 dose of trial vaccine, who had a valid pre-dose (baseline) and at least 1 valid post-dose measurement for immunogenicity and no major protocol violations. n= participants with data available at given time-point.
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End point type |
Secondary
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End point timeframe |
One month and six months post second dose (Day 120 and Day 270)
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No statistical analyses for this end point |
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End point title |
Seropositivity Rates for Multiple (2, 3 or 4) Dengue Serotypes | ||||||||||||||||||||||||||||||
End point description |
Seropositivity rate, defined as the percentage of participants seropositive, was derived from the titers of dengue-neutralizing antibodies. Seropositivity was defined as a reciprocal neutralizing titer ≥10. PPS: all participants seronegative to all serotypes of dengue virus at baseline who received at least 1 dose of trial vaccine, who had a valid pre-dose (baseline) and at least 1 valid post-dose measurement for immunogenicity and no major protocol violations. n= participants with data available at given time-point.
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End point type |
Secondary
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End point timeframe |
One month and six months post second dose (Day 120 and Day 270)
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No statistical analyses for this end point |
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End point title |
Percentage of Participants with Solicited Local (Injection Site) Adverse Events (AEs) (Diary Recorded) Following Each Vaccination by Severity | |||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Solicited local AEs (at injection site) were collected by participants using diary cards within 7 days after vaccination (Vac.) and included pain (none, mild: no interference with daily activity, moderate: interference with daily activity with or without treatment and severe: prevents daily activity with or without treatment), redness (erythema) (<2.5 cm, mild: 2.5-5 cm, moderate: >5 to <=10 cm, severe: >10 cm) and swelling (edema/induration) (<2.5 cm, mild: 2.5-5 cm, moderate: >5 to <=10 cm, severe: >10 cm). Safety Set included of all participants who received at least 1 dose of trial vaccine. Number analyzed is the number of participants with data available at the given timepoint. Only categories for which there was at least 1 participant are reported. n=participants with data available for given category. First vaccination= 1st vac.; Second vaccination=2nd vac.
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End point type |
Secondary
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End point timeframe |
Within 7 days after each vaccination
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No statistical analyses for this end point |
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End point title |
Percentage of Participants with Solicited Systemic Adverse Events (AEs) (Diary Recorded) Following Each Vaccination by Severity | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
End point description |
Solicited systemic AEs were collected by participants using diary cards within 14 days after vaccination and included fever, headache, tiredness or weakness (asthenia), feeling of discomfort (malaise) and muscle pain (myalgia). Severity scales for headache:none, mild:no interference with daily activity, moderate:interference with daily activity with or without treatment and severe:prevents normal activity with/without treatment. Severity scales for others:none, mild:no interference with daily activity, moderate:interference with daily activity and severe: prevents daily activity. systemic AE of fever (i.e. ≥38°C or ≥100.4°F) was derived from daily temperature reading recorded within 14 days after vaccination. Fever was excluded from overall count as no severity grading was applied for it. Safety Set:participants who received at least 1 dose of trial vaccine.Only categories for which there was at least 1 participant are reported. n= participants with data available for given category.
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End point type |
Secondary
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End point timeframe |
Within 14 days after each vaccination
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No statistical analyses for this end point |
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End point title |
Percentage of Participants with any Unsolicited Adverse Events (AEs) Following Each Vaccination | ||||||||||||||||||
End point description |
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. Safety Set included of all participants who received at least 1 dose of trial vaccine. Number analyzed is the number of participants with data available at the given timepoint. Only categories for which there was at least 1 participant are reported. n= participants with data available for given category.
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End point type |
Secondary
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End point timeframe |
Within 28 days after each vaccination
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No statistical analyses for this end point |
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End point title |
Percentage of Participants with Medically Attended AEs (MAAEs) Throughout the Study | ||||||||||||
End point description |
MAAEs were defined as AEs leading to a medical visit to or by a healthcare professional including visits to an emergency department, but not fulfilling seriousness criteria. Safety Set included of all participants who received at least 1 dose of trial vaccine.
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End point type |
Secondary
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End point timeframe |
From first vaccination (Day 1) through end of study (Day 270)
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No statistical analyses for this end point |
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End point title |
Percentage of Participants with Serious Adverse Events (SAEs) Throughout the Study | ||||||||||||
End point description |
An SAE was defined as any untoward medical occurrence or effect that 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. Safety Set included of all participants who received at least 1 dose of trial vaccine.
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End point type |
Secondary
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End point timeframe |
From first vaccination (Day 1) through end of study (Day 270)
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No statistical analyses for this end point |
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Adverse events information
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Timeframe for reporting adverse events |
Non-serious adverse events: Within 28 days of Vaccination; Serious adverse events (SAEs): From first vaccination (Day 1) through end of study (Day 270)
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Adverse event reporting additional 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.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.0
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tetravalent Dengue Vaccine (TDV)
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Reporting group description |
TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 2% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |