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Long-Term Safety and Antibody Persistence of TDV and Impact of a Booster Dose

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: NCT03999996
Recruitment Status : Active, not recruiting
First Posted : June 27, 2019
Last Update Posted : June 25, 2020
Sponsor:
Information provided by (Responsible Party):
Takeda

Brief Summary:
The purpose of this study is to describe antibody persistence for each of the 4 dengue serotypes for up to 36 months after the first vaccination in the primary vaccination series in the parent trials DEN-304 (NCT03423173) and DEN-315 (NCT03341637) (Month 15 in the current trial) and to describe the impact of a tetravalent dengue vaccine (TDV) booster dose vs placebo on antibody response for each of the 4 dengue serotypes at 1 month and 6 months post administration of the TDV booster or placebo (Month 16 and Month 21 respectively in the current trial).

Condition or disease Intervention/treatment Phase
Dengue Fever Biological: Tetravalent Dengue Vaccine (TDV) Biological: Placebo Phase 3

Detailed Description:

The vaccine tested in this study is Takeda's Tetravalent Dengue Vaccine Candidate (TDV). This study will look at the long-term antibody persistence and safety of Takeda's TDV in healthy adolescents and adults and will assess the impact of a booster dose.

The study has enrolled 365 healthy participants. Participants who previously received TDV in two parent trials (DEN-304 [NCT03423173] and DEN-315 [NCT03341637]), will be invited to participate in this follow-up trial. Participants will be assessed for antibody persistence and safety from Baseline (Month 0) through Month 15. At Month 15, eligible participants will be randomized in 1:1 ratio to one of two trial groups to receive TDV or placebo:

Group 1- TDV 0.5 mL subcutaneous (SC) injection at Month 15 Group 2- Takeda's tetravalent dengue placebo (dummy SC injection - this is a liquid that looks like the study drug but has no active ingredient), 0.5 mL, subcutaneous injection at Month 15

This multi-centre trial will be conducted in United States and Mexico. The overall time to participate in this study is up to 21 months. Participants will make 7 visits to the clinic including a final visit 6 months after last dose of study drug for a follow-up assessment.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 365 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: The study will be double-blinded, randomized, and placebo-controlled from Month 15 onwards.
Primary Purpose: Prevention
Official Title: A Phase 3, Follow-Up Trial to Evaluate Long-Term Safety and Antibody Persistence, and the Impact of a Booster Dose of a Tetravalent Dengue Vaccine Candidate in Healthy Adolescents and Adults in Areas Non-Endemic for Dengue
Actual Study Start Date : November 12, 2019
Estimated Primary Completion Date : March 7, 2022
Estimated Study Completion Date : March 7, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Dengue

Arm Intervention/treatment
Experimental: Takeda's Tetravalent Dengue Vaccine (TDV)
TDV 0.5 mL, injection, subcutaneously, once at Month 15.
Biological: Tetravalent Dengue Vaccine (TDV)
TDV subcutaneous injection

Placebo Comparator: Placebo
TDV placebo-matching 0.5 mL injection, subcutaneously, once at Month 15.
Biological: Placebo
Normal Saline (0.9% NaCl) subcutaneous injection




Primary Outcome Measures :
  1. Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Month 0 [ Time Frame: Day 1 (Month 0) ]
    GMTs of neutralizing antibodies will be measured by microneutralization test 50% [MNT50] for each of the 4 Dengue Serotypes for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at Baseline in the parent trials (DEN-304 and DEN-315). The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4.

  2. GMTs of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Month 12 [ Time Frame: Month 12 ]
    GMTs of neutralizing antibodies will be measured by microneutralization test 50% [MNT50] for each of the 4 Dengue Serotypes for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at Baseline in the parent trials (DEN-304 and DEN-315). The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4.

  3. GMTs of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Month 15 [ Time Frame: Month 15 ]
    GMTs of neutralizing antibodies will be measured by microneutralization test 50% [MNT50] for each of the 4 Dengue Serotypes for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at Baseline in the parent trials (DEN-304 and DEN-315). The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4.

  4. Percentage of Participants with Seropositivity for Each of the 4 Dengue Serotypes at Month 0 [ Time Frame: Day 1 (Month 0) ]
    Seropositivity rate, defined as the percentage of participants seropositive, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity rate will be calculated for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at Baseline in the parent trials (DEN-304 and DEN-315).

  5. Percentage of Participants with Seropositivity for Each of the 4 Dengue Serotypes at Month 12 [ Time Frame: Month 12 ]
    Seropositivity rate, defined as the percentage of participants seropositive, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity rate will be calculated for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at Baseline in the parent trials (DEN-304 and DEN-315).

  6. Percentage of Participants with Seropositivity for Each of the 4 Dengue Serotypes at Month 15 [ Time Frame: Month 15 ]
    Seropositivity rate, defined as the percentage of participants seropositive, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity rate will be calculated for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at Baseline in the parent trials (DEN-304 and DEN-315).

  7. Percentage of Participants with Seropositivity for Multiple (2, 3 or 4) Dengue Serotypes at Month 0 [ Time Frame: Day 1 (Month 0) ]
    Seropositivity rate for multiple Dengue serotypes, defined as the percentage of participants seropositive for more than one Dengue serotype, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. Seropositivity rate will be calculated for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at Baseline in the parent trials (DEN-304 and DEN-315).

  8. Percentage of Participants with Seropositivity for Multiple (2, 3 or 4) Dengue Serotypes at Month 12 [ Time Frame: Month 12 ]
    Seropositivity rate for multiple Dengue serotypes, defined as the percentage of participants seropositive for more than one Dengue serotype, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. Seropositivity rate will be calculated for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at Baseline in the parent trials (DEN-304 and DEN-315).

  9. Percentage of Participants with Seropositivity for Multiple (2, 3 or 4) Dengue Serotypes at Month 15 [ Time Frame: Month 15 ]
    Seropositivity rate for multiple Dengue serotypes, defined as the percentage of participants seropositive for more than one Dengue serotype, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. Seropositivity rate will be calculated for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at Baseline in the parent trials (DEN-304 and DEN-315).

  10. GMTs of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Month 16 [ Time Frame: Month 16 ]
    GMTs of neutralizing antibodies will be measured by microneutralization test 50% [MNT50] for each of the 4 Dengue Serotypes for participants randomized to Group 1 and 2 by trial group, by trial group and parent trial (DEN-304 and DEN-315), and by trial group and serostatus at Baseline in the parent trials (DEN-304 and DEN-315). The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4.

  11. GMTs of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Month 21 [ Time Frame: Month 21 ]
    GMTs of neutralizing antibodies will be measured by microneutralization test 50% [MNT50] for each of the 4 Dengue Serotypes for participants randomized to Group 1 and 2 by trial group, by trial group and parent trial (DEN-304 and DEN-315), and by trial group and serostatus at Baseline in the parent trials (DEN-304 and DEN-315). The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4.

  12. Percentage of Participants with Seropositivity for Each of the 4 Dengue Serotypes at Month 16 [ Time Frame: Month 16 ]
    Seropositivity rate, defined as the percentage of participants seropositive, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity rate will be calculated for participants randomized to Group 1 and 2 by trial group, by trial group and parent trial (DEN-304 and DEN-315), and by trial group and serostatus at Baseline in the parent trials (DEN-304 and DEN-315).

  13. Percentage of Participants with Seropositivity for Each of the 4 Dengue Serotypes at Month 21 [ Time Frame: Month 21 ]
    Seropositivity rate, defined as the percentage of participants seropositive, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. The 4 dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity rate will be calculated for participants randomized to Group 1 and 2 by trial group, by trial group and parent trial (DEN-304 and DEN-315), and by trial group and serostatus at Baseline in the parent trials (DEN-304 and DEN-315).

  14. Percentage of Participants with Seropositivity for Multiple (2, 3 or 4) Dengue Serotypes at Month 16 [ Time Frame: Month 16 ]
    Seropositivity rate for multiple Dengue serotypes, defined as the percentage of participants seropositive for more than one Dengue serotype, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. Seropositivity rate will be calculated for participants randomized to Group 1 and 2 by trial group, by trial group and parent trial (DEN-304 and DEN-315), and by trial group and serostatus at Baseline in the parent trials (DEN-304 and DEN-315).

  15. Percentage of Participants with Seropositivity for Multiple (2, 3 or 4) Dengue Serotypes at Month 21 [ Time Frame: Month 21 ]
    Seropositivity rate for multiple Dengue serotypes, defined as the percentage of participants seropositive for more than one Dengue serotype, is derived from the titers of dengue-neutralizing antibodies. Seropositivity is defined as a reciprocal neutralizing titer ≥10. Seropositivity rate will be calculated for participants randomized to Group 1 and 2 by trial group, by trial group and parent trial (DEN-304 and DEN-315), and by trial group and serostatus at Baseline in the parent trials (DEN-304 and DEN-315).


Secondary Outcome Measures :
  1. Geometric Mean Ratio (GMR) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes [ Time Frame: Month 0 versus (vs) Month 12; Month 4 in the parent trials (DEN-304 and DEN-315) vs Month 15 in the current trial; Month 9 in the parent trials (DEN-304 and DEN-315) vs Months 0 and 12 in the current trial ]
    GMR of neutralizing antibodies will be calculated for all participants, for all participants by parent trial (DEN-304 and DEN-315), and for all participants by serostatus at Baseline in the parent trials (DEN-304 and DEN-315).

  2. GMR of Neutralizing Antibodies for Each of the 4 Dengue Serotypes [ Time Frame: Month 4 in the parent trials (DEN-304 and DEN-315) vs Month 16 in the current trial; Month 15 vs Month 16; Month 15 vs Month 21; Month 16 vs Month 21; Month 4 in the parent trials (DEN-304 and DEN-315) vs Month 21 in the current trial ]
    GMR of neutralizing antibodies will be calculated for participants randomized to Group 1 and 2 by trial group, by trial group and parent trial (DEN-304 and DEN-315), and by trial group and serostatus at Baseline in the parent trials (DEN-304 and DEN-315).

  3. Percentage of Participants with Solicited Local Injection Site Adverse Events (AEs) by Severity, by Trial Group [ Time Frame: Days 1 through 7 after vaccination at Month 15 ]
    Solicited local AEs at injection site are defined as pain, erythema and swelling that occurred within 7 days after vaccination at Month 15.

  4. Percentage of Participants with Solicited Systemic Adverse Events (AEs) by Severity, by Trial Group [ Time Frame: Days 1 through 14 after vaccination at Month 15 ]
    Solicited systemic AEs are defined as fever, headache, asthenia, malaise and myalgia that occurred within 14 days after vaccination at Month 15.

  5. Percentage of Participants with any Unsolicited Adverse Events (AEs) [ Time Frame: Up to 28 days (Day of Vaccination+27 Subsequent Days) after TDV/Placebo dose at Month 15 ]
    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.

  6. Percentage of Participants with Medically Attended AEs (MAAEs) [ Time Frame: Month 15 through Month 21 ]
    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.

  7. Percentage of Participants with Serious Adverse Events (SAEs) at Month 0 through Month 15 [ Time Frame: Month 0 through Month 15 prior to administration of the TDV booster or placebo ]
    A 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.

  8. Percentage of Participants with SAEs at Month 15 through Month 21 [ Time Frame: Month 15 after administration of the TDV booster or placebo through Month 21 ]
    A 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   13 Years to 63 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

1. Male or female participants (irrespective of serostatus at Baseline in the parent trials (DEN-304 [(NCT03423173)] and DEN-315 [NCT03341637]) who received at least one dose of Takeda's tetravalent dengue vaccine candidate (TDV) in the parent trials and have data from at least one blood draw post-vaccination.

Exclusion Criteria:

  1. Participants with a prolonged period of habitation (=1 year) in a dengue endemic area within the 2 years prior to Day 1 (Month 0).
  2. Previous and planned vaccination (during the trial conduct), against any flavivirus including dengue (other than Takeda's TDV), yellow fever (YF), Japanese encephalitis (JE) viruses or tick-borne encephalitis.

Booster Criteria:

  1. Participants for whom Baseline serostatus is not defined in the parent trials (DEN-304 [(NCT03423173)] and DEN-315 [NCT03341637]).
  2. Participants with any history of progressive or severe neurologic disorder, seizure disorder or neuro-inflammatory disease (eg, Guillain-Barré syndrome).
  3. Known or suspected impairment/alteration of immune function, including:

    1. Chronic use of oral steroids (equivalent to 20 mg/day prednisone =12 weeks/=2 mg/kg body weight/day prednisone =2 weeks) within 60 days prior to Month 15; use of inhaled, intranasal, or topical corticosteroids is allowed.
    2. Receipt of parenteral steroids (equivalent to 20 mg/day prednisone =12 weeks/= 2 mg/kg body weight/day prednisone =2 weeks) within 60 days prior to Month 15.
    3. Administration of immunoglobulins and/or any blood products within the 3 months prior to administration of the TDV booster or placebo at Month 15; consider whether applicable as an exclusion criterion or criterion for delay.
    4. Receipt of immunostimulants within 60 days prior to Month 15.
    5. Immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within 6 months prior to Month 15.
    6. Known human immunodeficiency virus (HIV) infection or HIV-related disease.
    7. Hepatitis C virus infection.
    8. Genetic immunodeficiency.
  4. Abnormalities of splenic or thymic function.
  5. Participants with a known bleeding diathesis, or any condition that may be associated with a prolonged bleeding time.
  6. Participants with history of current or previous infection with a flavivirus such as dengue, Zika, YF, JE, West Nile fever, tick-borne encephalitis or Murray Valley encephalitis and participants with a prolonged period of habitation (=1 year) in a dengue endemic area during trial conduct.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03999996


Locations
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United States, Alabama
Synexus - Optimal Research - Huntsville
Huntsville, Alabama, United States, 35802
United States, Illinois
Synexus - Optimal Research - Peoria
Peoria, Illinois, United States, 61614
United States, Kansas
Heartland Research Associates LLC
Newton, Kansas, United States, 67114
United States, Maryland
Optimal Research
Rockville, Maryland, United States, 20850
United States, Minnesota
Synexus Clinical Research US, Inc. Minneapolis
Richfield, Minnesota, United States, 55423
United States, Missouri
Synexus Clinical Research US, Inc. - St. Louis
Saint Louis, Missouri, United States, 63141
United States, Nebraska
Synexus Clinical Research US, Inc. - Omaha
Omaha, Nebraska, United States, 68144
United States, Utah
Advanced Clinical Research - Meridian - ERN-PPDS
Taylorsville, Utah, United States, 84123
Mexico
Instituto Nacional de Pediatria
Mexico City, Mexico, 4530
CAIMED Investigacion en Salud, S. A. de C. V.
Mexico City, Mexico, 6760
Sponsors and Collaborators
Takeda
Investigators
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Study Director: Medical Director Takeda
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Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT03999996    
Other Study ID Numbers: DEN-303
First Posted: June 27, 2019    Key Record Dates
Last Update Posted: June 25, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available for all interventional studies after applicable marketing approvals and commercial availability have been received (or program is completely terminated), an opportunity for the primary publication of the research and final report development has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Takeda:
Vaccine
Additional relevant MeSH terms:
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Dengue
Arbovirus Infections
Virus Diseases
Flavivirus Infections
Flaviviridae Infections
RNA Virus Infections
Hemorrhagic Fevers, Viral