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    Summary
    EudraCT Number:2018-003979-34
    Sponsor's Protocol Code Number:DEN-301
    Clinical Trial Type:Outside EU/EEA
    Date on which this record was first entered in the EudraCT database:2018-12-13
    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 number2018-003979-34
    A.3Full title of the trial
    Phase III, Double-Blind, Randomized, Placebo-Controlled Trial to Investigate the Efficacy, Safety
    and Immunogenicity of a Tetravalent Dengue Vaccine (TDV) Administered Subcutaneously in
    Healthy Children Aged 4 – 16 Years Old
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Trial to Investigate Efficacy, Safety and Immunogenicity of Takeda's Tetravalent Dengue Vaccine in Healthy Children
    A.4.1Sponsor's protocol code numberDEN-301
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02747927
    A.5.3WHO Universal Trial Reference Number (UTRN)U1111-1166-8401
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/180/2017
    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 pointVianney Tricou
    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.5.4Telephone number+6598578438
    B.5.6E-mailVianney.tricou@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 No
    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 nameTetravalent Dengue Vaccine Candidate (TDV)
    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 INNTDV CHIMERIC DENGUE VIRUS SEROTYPE 1
    D.3.9.2Current sponsor codeTDV-1
    D.3.9.3Other descriptive nameTDV CHIMERIC DENGUE VIRUS SEROTYPE 1 (TDV-1)
    D.3.9.4EV Substance CodeSUB188351
    D.3.10 Strength
    D.3.10.1Concentration unit PFU/ml plaque forming unit(s)/millilitre
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number3980
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTDV DENGUE VIRUS SEROTYPE 2
    D.3.9.2Current sponsor codeTDV-2
    D.3.9.3Other descriptive nameTDV DENGUE VIRUS SEROTYPE 2 (TDV-2)
    D.3.9.4EV Substance CodeSUB188352
    D.3.10 Strength
    D.3.10.1Concentration unit PFU/ml plaque forming unit(s)/millilitre
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number1000
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTDV CHIMERIC DENGUE VIRUS SEROTYPE 3
    D.3.9.2Current sponsor codeTDV-3
    D.3.9.3Other descriptive nameTDV CHIMERIC DENGUE VIRUS SEROTYPE 3 (TDV-3)
    D.3.9.4EV Substance CodeSUB188353
    D.3.10 Strength
    D.3.10.1Concentration unit PFU/ml plaque forming unit(s)/millilitre
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number20000
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTDV CHIMERIC DENGUE VIRUS SEROTYPE 4
    D.3.9.2Current sponsor codeTDV-4
    D.3.9.3Other descriptive nameTDV CHIMERIC DENGUE VIRUS SEROTYPE 4 (TDV-4)
    D.3.9.4EV Substance CodeSUB188354
    D.3.10 Strength
    D.3.10.1Concentration unit PFU/ml plaque forming unit(s)/millilitre
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number63200
    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
    The purpose of this study is to evaluate the efficacy of 2 doses of Tetravalent Dengue Vaccine Candidate (TDV) in preventing symptomatic dengue fever of any severity and due to any of the four dengue virus serotypes in 4 to 16 year old participants.
    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
    To evaluate the efficacy of 2 doses of TDV in preventing symptomatic dengue fever of any severity and due to any of the 4 dengue virus serotypes in 4-16 year old subjects.
    E.2.2Secondary objectives of the trial
    Efficacy:
    • To assess the efficacy of TDV against individual dengue serotypes.
    • To assess the efficacy of TDV in preventing symptomatic dengue fever of any severity by dengue exposure status at baseline.
    • To assess the efficacy of TDV in preventing hospitalization due to virologically-confirmed dengue fever.
    • To assess the efficacy of TDV in preventing severe dengue induced by any dengue serotype.

    Safety:
    • To describe the safety of TDV.
    • To describe the reactogenicity of TDV in a subset of subjects.

    Immunogenicity:
    • To assess the immunogenicity of TDV in a subset of subjects.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. The subject is aged 4 to 16 years, inclusive, at the time of randomization.
    2. Individuals who are in good health at the time of entry into the trial as determined by medical history, physical examination (including vital signs) and clinical judgment of the Investigator.
    3. The subject and/or the subject’s parent/guardian signs and dates an assent/written informed consent form where applicable, and any required privacy authorization prior to the initiation of any trial procedures, after the nature of the trial has been explained according to local regulatory requirements.
    4. Individuals who can comply with trial procedures and are available for the duration of follow-up.
    E.4Principal exclusion criteria
    1. Febrile illness (temperature ≥38°C) or moderate or severe acute illness or infection at the time of randomization.
    2. History or any illness that, in the opinion of the Investigator, might interfere with the results of the trial or pose an additional risk to the subject due to participation in the trial, including but not limited to:
    a. Known hypersensitivity or allergy to any of the vaccine components.
    b. Female subjects (post-menarche) who are pregnant or breastfeeding.
    c. Individuals with any serious chronic or progressive disease according to judgment of the Investigator (eg, neoplasm, insulin-dependent diabetes, cardiac, renal or hepatic disease, neurologic or seizure disorder or Guillain-Barré syndrome).
    d. Known or suspected impairment/alteration of immune function, including:
    i. 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 Day 1 (Month 0) (use of inhaled, intranasal, or topical corticosteroids is allowed).
    ii. 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 Day 1 (Month 0).
    iii. Administration of immunoglobulins and/or any blood products within the 3 months prior to Day 1 (Month 0) or planned administration during the trial.
    iv. Receipt of immunostimulants within 60 days prior to Day 1 (Month 0).
    v. Immunosuppressive therapy such as anti-cancer chemotherapy or radiation
    therapy within 6 months prior to Day 1 (Month 0).
    vi. Human Immunodeficiency Virus (HIV) infection or HIV-related disease.
    vii. Genetic immunodeficiency.
    3. Receipt of any other vaccine within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to Day 1 (Month 0) or planning to receive any vaccine within 28 days after Day 1 (Month 0).
    4. Participation in any clinical trial with another investigational product 30 days prior to Day 1 (Month 0) or intent to participate in another clinical trial at any time during the conduct of this trial.
    5. Previous participation in any clinical trial of a dengue candidate vaccine, or previous receipt of a dengue vaccine.
    6. First degree relatives of individuals involved in trial conduct.
    7. Females of childbearing potential who are sexually active, and who have not used any of the acceptable contraceptive methods for at least 2 months prior to Day 1 (Month 0).
    a. Of childbearing potential is defined as status post onset of menarche and not meeting any of the following conditions: bilateral tubal ligation (at least 1 year previously), bilateral oophorectomy (at least 1 year previously) or hysterectomy.
    b. Acceptable birth control methods are defined as 1 or more of the following:
    i. Hormonal contraceptive (such as oral, injection, transdermal patch, implant, cervical ring).
    ii. Barrier (condom with spermicide or diaphragm with spermicide) each and every time during intercourse.
    iii. Intrauterine device (IUD).
    iv. Monogamous relationship with vasectomized partner (partner must have been vasectomized for at least six months prior to Day 1 [Month 0]). Other contraceptive methods may be considered in agreement with the Sponsor and will be approved by the appropriate ethics committee.
    8. Females of childbearing potential who are sexually active, and who refuse to use an acceptable contraceptive method up to 6 weeks post-second vaccination.
    9. Deprived of freedom by administrative or court order, or in an emergency setting, or hospitalized involuntarily.
    10. Current alcohol abuse or drug addiction that may interfere with the subject’s ability to comply with trial procedures.
    11. Identified as an employee of the Investigator or trial center, with direct involvement in the proposed trial or other trials under the direction of that Investigator or trial center.
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy
    Vaccine efficacy (VE) of 2 doses of TDV in preventing virologically-confirmed dengue fever induced by any dengue serotype occurring from 30 days post-second vaccination (Day 120 [Month 4]) until the end of Part 1, with VE defined as 1 – (λV/λC) (where λV and λC denote the hazard rates for the TDV and placebo arms, respectively).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Time Frame: 30 days post-second vaccination (Day 120) until the end of Part 1 (120 cases of dengue fever are confirmed and minimum duration of subject follow-up of 12 months post-second vaccination)
    E.5.2Secondary end point(s)
    Efficacy
    • VE of 2 doses of TDV in preventing virologically-confirmed dengue fever induced by each dengue serotype from 30 days post-second vaccination (Day 120 [Month 4]) until the end of Part 2.
    • VE of 2 doses of TDV in preventing virologically-confirmed dengue fever induced by any dengue serotype from 30 days post-second vaccination (Day 120 [Month 4]) until the end of Part 2 in subjects dengue seronegative at baseline.
    • VE of 2 doses of TDV in preventing virologically-confirmed dengue fever induced by any dengue serotype from 30 days post-second vaccination (Day 120 [Month 4]) until the end of Part 2 in subjects dengue seropositive at baseline.
    • VE of 2 doses of TDV in preventing hospitalization due to virologically-confirmed dengue fever induced by any dengue serotype from 30 days post-second vaccination (Day 120 [Month 4]) until the end of Part 2.
    • VE of 2 doses of TDV in preventing virologically-confirmed severe dengue fever induced by any dengue serotype from 30 days post-second vaccination (Day 120 [Month 4]) until the end of Part 2.

    Safety
    Subset (post-first and post-second vaccinations):
    • Frequency and severity of solicited local (injection site) AEs for 7 days (day of vaccination + 6 subsequent days) and solicited systemic AEs for 14 days (day of vaccination + 13 subsequent days) post-vaccination.
    • Percentage of subjects with any unsolicited AEs for 28 days (day of vaccination + 27 subsequent days) post-vaccination.
    All subjects:
    • Percentage of subjects with serious adverse events (SAEs) during Parts 1 and 2, Part 1 and Part 2 combined.
    • Percentage of subjects with fatal SAEs and related SAEs during the first and second half of Part 3.

    Immunogenicity
    Subset (post-first and post-second vaccinations):
    • Seropositivity rate (% of seropositive subjects) for each of the 4 dengue serotypes at pre-vaccination on Day 1 (Month 0), post-first vaccination on Day 30 (Month 1), pre-vaccination on Day 90 (Month 3); post-second vaccination at Day 120 (Month 4), Day 270 (Month 9), Day 450 (Month 15), and then annually.
    • Seropositivity rate (% of seropositive subjects) for multiple (any 2, 3 or 4) dengue serotypes at pre-vaccination on Day 1 (Month 0), post-first vaccination on Day 30 (Month 1), pre-vaccination on Day 90 (Month 3); post-second vaccination at Day 120 (Month 4), Day 270 (Month 9), Day 450 (Month 15), and then annually. Note: Seropositivity is defined as a reciprocal neutralizing titer ≥10.
    • Geometric mean titers (GMTs) of neutralizing antibodies (microneutralization test [MNT]) for each dengue serotype at pre-vaccination on Day 1 (Month 0), post-first vaccination on Day 30 (Month 1), pre-vaccination on Day 90 (Month 3); post-second vaccination at Day 120 (Month 4), Day 270 (Month 9), Day 450 (Month 15), and then annually.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Multiple time points occurring 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 Yes
    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
    Brazil
    Colombia
    Dominican Republic
    Nicaragua
    Panama
    Philippines
    Sri Lanka
    Thailand
    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
    LSLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months9
    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: 20100
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 15075
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 5025
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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
    Children between 4 and 16 years of age.
    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 20100
    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: Philippines
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