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    Summary
    EudraCT Number:2023-000027-36
    Sponsor's Protocol Code Number:DEN-303
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2023-02-03
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    H.4 THIRD COUNTRY IN WHICH THE TRIAL WAS FIRST AUTHORISED
    Expand All   Collapse All
    A. Protocol Information
    A.2EudraCT number2023-000027-36
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Long-Term Safety and Antibody Persistence of TDV and the Impact of a Booster Dose
    A.4.1Sponsor's protocol code numberDEN-303
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03999996
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorTakeda Vaccines, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportTakeda Vaccines, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTakeda Vaccines, Inc.
    B.5.2Functional name of contact pointStudy Director
    B.5.3 Address:
    B.5.3.1Street Address40 Landsdowne Street
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeMA 02139
    B.5.3.4CountryUnited States
    B.5.6E-mailTrialDisclosures@takeda.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Qdenga®
    D.2.1.1.2Name of the Marketing Authorisation holderTakeda GmBH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameDengue Tetravalent Vaccine (Live, Attenuated)
    D.3.2Product code TAK-003
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDengue virus serotype 1 (live, attenuated)
    D.3.9.2Current sponsor codeTDV-1
    D.3.9.4EV Substance CodeSUB217716
    D.3.10 Strength
    D.3.10.1Concentration unit log10 PFU/dose log10 plaque forming unit(s)/dose
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number3.3
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDengue virus serotype 2 (live, attenuated)
    D.3.9.2Current sponsor codeTDV-2
    D.3.10 Strength
    D.3.10.1Concentration unit log10 PFU/dose log10 plaque forming unit(s)/dose
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number2.7
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDengue virus serotype 3 (live, attenuated)
    D.3.9.2Current sponsor codeTDV-3
    D.3.10 Strength
    D.3.10.1Concentration unit log10 PFU/dose log10 plaque forming unit(s)/dose
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number4.0
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDengue virus serotype 4 (live, attenuated)
    D.3.9.2Current sponsor codeTDV-4
    D.3.10 Strength
    D.3.10.1Concentration unit log10 PFU/dose log10 plaque forming unit(s)/dose
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number4.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) Yes
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Dengue fever
    E.1.1.1Medical condition in easily understood language
    Dengue fever is caused by infection with dengue virus, a RNA virus that occurs as 4 recognized serotypes: DENV-1, -2, -3, or -4. These viruses are transmitted from human to human by mosquitoes.
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10012312
    E.1.2Term Dengue fever virus infection
    E.1.2System Organ Class 100000004862
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    1. To describe antibody persistence for each of the 4 dengue serotypes for up to 63 months after the first vaccination in the primary vaccination series in parent trial DEN-315 (Mexico) and for up to 36 months after the first vaccination in the primary vaccination series for subjects from parent trial DEN-304 (United States).
    2. To describe the impact of a 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.
    E.2.2Secondary objectives of the trial
    1. Describing overall trend in antibody decay of all 4 dengue serotypes from values obtained after primary vaccination series in the parent trials DEN-315 (Mexico), 63 months after first vaccination and DEN-304 (US), 36 months after first vaccination.
    2. Describing the impact of a TDV booster on antibody response for each of 4 dengue serotypes for up to 69 months following first vaccination in the primary vaccination series for participants from parent trial DEN-315 (Mexico) and for up to 42 months following first vaccination in primary vaccination for participants from parent trial DEN-304 (US).
    3. Describing long-term safety of Takeda’s TDV for up to 63 months in previously vaccinated participants from parent trial DEN-315 (Mexico) and for up to 36 months in previously vaccinated participants from parent trial DEN-304 (US).
    4. Assessing safety for 6 months following administration of TDV booster or placebo in Groups 1 and 2, respectively.
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal exclusion criteria
    1. Participants with a prolonged period of habitation (≥1 year) in a dengue endemic area within the 2 years prior to Visit 1 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 Exclusion 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:
    a) 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 42 for participants from parent trial DEN-315 (Mexico)/ Month 15 for participants from parent trial DEN-304 (US); use of inhaled, intranasal, or topical corticosteroids is allowed.
    b) 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 42 for participants from parent trial DEN-315 (Mexico)/ Month 15 for participants from parent trial DEN-304 (US).
    c) Administration of immunoglobulins and/or any blood products within the 3 months prior to administration of the TDV booster or placebo at Month 42 for participants from parent trial DEN-315 (Mexico)/ Month 15 for participants from parent trial DEN-304 (US); consider whether applicable as an exclusion criterion or criterion for delay.
    d) Receipt of immunostimulants within 60 days prior to Month 42 for participants from parent trial DEN-315 (Mexico)/ Month 15 for participants from parent trial DEN-304 (US).
    e) Immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within 6 months prior to Month 42 for participants from parent trial DEN-315 (Mexico) / Month 15 for participants from parent trial DEN-304 (US).
    f) Known human immunodeficiency virus (HIV) infection or HIV-related disease.
    g) Hepatitis C virus infection.
    h) 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.
    E.5 End points
    E.5.1Primary end point(s)
    1. Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes Prior to the Booster Dose at Month 0 (Day 1)
    2. Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes Prior to the Booster Dose at Month 12
    3. Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes Prior to the Booster Dose at Month 15 (US)
    4. Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes Prior to the Booster Dose at Month 42 (Mexico)
    5. Percentage of Participants Seropositive for Each of the 4 Dengue Serotypes Prior to the Booster Dose at Month 0 (Day 1)
    6. Percentage of Participants Seropositive for Each of the 4 Dengue Serotypes Prior to the Booster Dose at Month 12
    7. Percentage of Participants Seropositive for Each of the 4 Dengue Serotypes Prior to the Booster Dose at Month 15 (US)
    8. Percentage of Participants Seropositive for Each of the 4 Dengue Serotypes Prior to the Booster Dose at Month 42 (Mexico)
    9. Percentage of Participants Seropositive for Multiple (2, 3 or 4) Dengue Serotypes Prior to the Booster Dose at Month 0 (Day 1)
    10. Percentage of Participants Seropositive for Multiple (2, 3 or 4) Dengue Serotypes Prior to the Booster Dose at Month 12
    11. Percentage of Participants Seropositive for Multiple (2, 3 or 4) Dengue Serotypes Prior to the Booster Dose Month 15 (US)
    12. Percentage of Participants Seropositive for Multiple (2, 3 or 4) Dengue Serotypes Prior to the Booster Dose at Month 42 (Mexico)
    13. GMTs of Neutralizing Antibodies for Each of the 4 Dengue Serotypes Post-Booster Dose at 1 Month Post-Booster Dose at Month 16 (US)
    14. GMTs of Neutralizing Antibodies for Each of the 4 Dengue Serotypes Post-Booster Dose at 1 Month Post-Booster Dose at Month 43 (Mexico)
    15. GMTs of Neutralizing Antibodies for Each of the 4 Dengue Serotypes Post-Booster Dose at 6 Months Post-Booster Dose at Month 21 (US)
    16. GMTs of Neutralizing Antibodies for Each of the 4 Dengue Serotypes Post-Booster Dose at 6 Months Post-Booster Dose at Month 48 (Mexico)
    17. Percentage of Participants Seropositive for Each of the 4 Dengue Serotypes Post-Booster Dose at 1 Month Post-Booster Dose at Month 16 (US)
    18. Percentage of Participants Seropositive for Each of the 4 Dengue Serotypes Post-Booster Dose at 1 Month Post-Booster Dose at Month 43 (Mexico)
    19. Percentage of Participants Seropositive for Each of the 4 Dengue Serotypes Post-Booster Dose at 6 Months Post-Booster Dose at Month 21 (US)
    20. Percentage of Participants Seropositive for Each of the 4 Dengue Serotypes Post-Booster Dose at 6 Months Post-Booster Dose at Month 48 (Mexico)
    21. Percentage of Participants Seropositive for Multiple (2, 3 or 4) Dengue Serotypes Post-Booster Dose at 1 Month Post-Booster Dose at Month 16 (US)
    22. Percentage of Participants Seropositive for Multiple (2, 3 or 4) Dengue Serotypes Post-Booster Dose at 1 Month Post-Booster Dose at Month 43 (Mexico)
    23. Percentage of Participants Seropositive for Multiple (2, 3 or 4) Dengue Serotypes Post-Booster Dose at 6 Months Post-Booster Dose at Month 21 (US)
    24. Percentage of Participants Seropositive for Multiple (2, 3 or 4) Dengue Serotypes Post-Booster Dose at 6 Months Post-Booster Dose at Month 48 (Mexico)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Multiple time points up to Month 48 as stated in Section E.5.1
    E.5.2Secondary end point(s)
    1. Geometric Mean Ratio (GMR) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes for all Participants Prior to the Booster Dose at Month 0 vs Month 12 in the current trial, Month 4 in the parent trials vs Month 15 (US) and Month 42 (Mexico) in the current trials, Month 9 in the parent trials vs Month 0 and Month 12 in the current trial
    2. GMR of Neutralizing Antibodies for Each of the 4 Dengue Serotypes Post-booster Dose at Month 4 in the parent trials vs 1 and 6 months post-booster dose in the current trial; Month 15 (US)/Month 42 (Mexico) vs 1 month post-booster dose; Month 15 (US)/Month 42 (Mexico) vs 6 month post-booster dose; 1 vs 6 month post-booster dose
    3. Percentage of Participants with Solicited Local Injection Site Adverse Events (AEs) by Severity, Post-booster Dose at Days 1 through 7 post-booster dose at Month 15 (US) and Month 42 (Mexico)
    4. Percentage of Participants with Solicited Systemic AEs by Severity Post-booster Dose at Days 1 through 14 post-booster dose at Month 15 (US) and Month 42 (Mexico)
    5. Percentage of Participants with any Unsolicited AEs Post-booster Dose at Days 1 through 28 post-booster dose at Month 15 (US) and Month 42 (Mexico)
    6. Percentage of Participants with any Medically Attended AEs (MAAEs) Post-booster Dose at Month 15 post-booster dose through Month 21 (US); Month 42 post-booster dose through Month 48 (Mexico)
    7. Percentage of Participants with any Serious Adverse Events (SAEs) Prior to the Booster Dose at Month 0 through Month 15 (US) and Month 42 (Mexico)
    8. Percentage of Participants with any SAEs Post-Booster Dose at Month 15 post-booster dose after vaccination through Month 21 (US); Month 42 post-booster dose after vaccination through Month 48 (Mexico)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Multiple time points up to Month 48 as stated in Section E.5.2
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis Yes
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 Will this trial be conducted at a single site globally? No
    E.8.4 Will this trial be conducted at multiple sites globally? Yes
    E.8.6 Trial involving sites outside the EEA
    E.8.6.2Trial being conducted completely outside of the EEA Yes
    E.8.6.3Specify the countries outside of the EEA in which trial sites are planned
    Mexico
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 79
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 79
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 286
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients No
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Few subjects being pediatric age group, were not able to give consent, thus needed parent/caregiver to sign consent.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 365
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    H.4 Third Country in which the Trial was first authorised
    H.4.1Third Country in which the trial was first authorised: United States
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