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Immunogenicity and Safety of Tetravalent Dengue Vaccine Candidate (TDV) in Flavivirus-Naïve and Dengue-Immune 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: NCT03746015
Recruitment Status : Completed
First Posted : November 19, 2018
Last Update Posted : February 25, 2022
Sponsor:
Information provided by (Responsible Party):
Takeda

Study Description
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Brief Summary:
The purpose of this study is to assess the neutralizing antibody response against each dengue serotype post-vaccination.

Condition or disease Intervention/treatment Phase
Dengue Fever Biological: Takeda's Tetravalent Dengue Vaccine Candidate (TDV) Phase 2

Detailed Description:

The vaccine being tested in this study is Takeda's Tetravalent Dengue Vaccine Candidate (TDV). TDV is being tested to protect people against dengue fever. This study will look at the immunogenicity and safety of TDV in flavivirus-naïve and dengue-immune adults.

The study will enroll approximately 44 patients. Participants will be categorized into two groups based on results from serological testing performed by the trial center outside the scope of this trial (up to 70 days [10 weeks] prior to Day 1 [Month 0]):

Group 1: Flavivirus-Naïve Participants Group 2: Dengue-Immune Participants

All participants will receive subcutaneous injection of TDV on Day 1 (Month 0) and Day 90 (Month 3).

This trial will be conducted in the United States. The overall time to participate in this study is 12 months. Participants will make multiple visits to the clinic, and 9 months after last dose of study drug for a follow-up assessment.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 179 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: An Open-Label, Phase 2 Trial to Investigate the Humoral and Cell-Mediated Immune Responses and Safety of a Tetravalent Dengue Vaccine Candidate (TDV) Administered Subcutaneously in Flavivirus-Naïve and Dengue-Immune Healthy Adults
Actual Study Start Date : December 28, 2018
Actual Primary Completion Date : March 1, 2021
Actual Study Completion Date : March 1, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Dengue Vaccines

Arms and Interventions
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Arm Intervention/treatment
Experimental: Takeda's Tetravalent Dengue Vaccine Candidate (TDV) 0.5 mL
TDV 0.5 mL, subcutaneous (SC) injection on Day 1 (Month 0) and Day 90 (Month 3) in flavivirus-naïve participants (Group 1) and dengue-immune participants (Group 2). TDV comprised of 1 molecularly characterized, attenuated dengue virus strain and 3 chimeric dengue virus strains: TDV-1, TDV-2, TDV-3 and TDV-4 containing not less than 3.3, 2.7, 4.0, and 4.5 log10 plaque forming units (PFU) respectively.
 Biological: Takeda's Tetravalent Dengue Vaccine Candidate (TDV)
Tetravalent Dengue Vaccine (TDV) subcutaneous injection


Outcome Measures
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Primary Outcome Measures :
  1. Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 15 [ Time Frame: Day 15 ]
    GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by microneutralization test 50% (MNT50).

  2. Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 30 (Month 1) [ Time Frame: Day 30 (Month 1) ]
    GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.

  3. Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 60 (Month 2) [ Time Frame: Day 60 (Month 2) ]
    GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.

  4. Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 90 (Month 3) [ Time Frame: Day 90 (Month 3) ]
    GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.

  5. Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 105 [ Time Frame: Day 105 ]
    GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.

  6. Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 120 (Month 4) [ Time Frame: Day 120 (Month 4) ]
    GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.

  7. Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 150 (Month 5) [ Time Frame: Day 150 (Month 5) ]
    GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.

  8. Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 180 (Month 6) [ Time Frame: Day 180 (Month 6) ]
    GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.

  9. Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 270 (Month 9) [ Time Frame: Day 270 (Month 9) ]
    GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.

  10. Geometric Mean Neutralizing Antibody Titer (GMT) for Each of the Four Dengue Serotypes at Day 360 (Month 12) [ Time Frame: Day 360 (Month 12) ]
    GMT of neutralizing antibodies will be measured for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.


Secondary Outcome Measures :
  1. Percentage of Participants with Interferon-gamma (IFN-γ) Enzyme-linked Immunospot (ELISpot) Responses to Tetravalent Dengue Vaccine (TDV) [ Time Frame: Days 15, 30 (Month 1), 60 (Month 2), 90 (Month 3), 105, 120 (Month 4), 150 (Month 5), 180 (Month 6), 270 (Month 9), 360 (Month 12) ]
    IFN-γ ELISpot response that is >3 times higher compared with baseline (no peptide) and ≥50 spots per 10^6 peripheral blood mononuclear cells (PBMC) is defined as cellular immune response.

  2. Number of Spot Forming Cells [SFC]/10^6 Peripheral Blood Mononuclear Cells (PBMC) of IFN-γ ELISpot Responses to TDV [ Time Frame: Days 15, 30 (Month 1), 60 (Month 2), 90 (Month 3), 105, 120 (Month 4), 150 (Month 5), 180 (Month 6), 270 (Month 9), 360 (Month 12) ]
    IFN-γ ELISpot response that is >3 times higher compared with baseline (no peptide) and ≥50 spots per 10^6 PBMC is defined as cellular immune response.

  3. Phenotype Characterization of Cellular Immune Response to TDV Assessed by Intracellular Cytokine Staining (ICS) [ Time Frame: Days 15, 30 (Month 1), 60 (Month 2), 90 (Month 3), 105, 120 (Month 4), 150 (Month 5), 180 (Month 6), 270 (Month 9), 360 (Month 12) ]
    Phenotype characterization of cellular immune response will be performed in a subset of participants with IFN- γ ELISPOT responses >500 SFC/10^6 cells and availability of sufficient cells. Markers will include cluster of differentiation (CD) 4, CD8, IFN-γ, tumor necrosis factor-alpha (TNF-α) and interleukin-2 (IL-2).

  4. Percentage of Participants with Vaccine Viremia for Each of the Four Vaccine Strains after Vaccination [ Time Frame: Days 6, 9, 12, 15, 30 (Month 1), 90 (Month 3), 96, 99, 102, 105, 120 (Month 4) ]
    Vaccine viremia will be assessed for each of the four vaccine strain serotypes: TDV-1, TDV-2, TDV-3 and TDV-4. Vaccine viral ribonucleic acid (RNA) was detected by a quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assay.

  5. Duration of Vaccine Viremia for Each of the Four Vaccine Strains after Vaccination [ Time Frame: Days 6, 9, 12, 15, 30 (Month 1), 90 (Month 3), 96, 99, 102, 105, 120 (Month 4) ]
    The duration of vaccine viremia for each vaccine strain is defined as the date when vaccine viremia is last detected (positive result) to date when vaccine viremia is first detected (positive result) + 1 day. It will be assessed for each of the four vaccine strains: TDV-1, TDV-2, TDV-3 and TDV-4. Vaccine viral RNA was detected by qRT-PCR assay.

  6. Level of Vaccine Viremia for Each of the Four Vaccine Strains after Vaccination [ Time Frame: Days 6, 9, 12, 15, 30 (Month 1), 90 (Month 3), 96, 99, 102, 105, 120 (Month 4) ]
    Vaccine viremia will be assessed for each of the four vaccine strain serotypes: TDV-1, TDV-2, TDV-3 and TDV-4. Vaccine viral RNA was detected by qRT-PCR assay.

  7. Number of Participants with Solicited Local (Injection Site) Reactions Following Vaccination [ Time Frame: Within 7 days after either of the vaccination given on Day 1 (Month 0) or 90 (Month 3) ]
    Solicited local AEs (at injection site) will be collected by participants using diary cards within 7 days after vaccination and will include 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)].

  8. Number of Participants with Solicited Systemic Reactions Following Vaccination [ Time Frame: Within 14 days after either of the vaccination given on Day 1 (Month 0) or 90 (Month 3) ]
    Solicited systemic AEs will be collected by participants using diary cards within 14 days after vaccination and will include fever, headache, asthenia, malaise and myalgia. Severity grades are: 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). A systemic AE of fever (defined as body temperature ≥ 100.4°F regardless of method taken) will be derived from a daily temperature reading recorded within 14 days after vaccination.

  9. Number of Participants with at Least one Unsolicited Adverse Events (AEs) Following Vaccination [ Time Frame: Within 28 days after either of the vaccination given on Day 1 (Month 0) or 90 (Month 3) ]
    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.

  10. Number of Participants with Serious Adverse Events (SAEs) [ Time Frame: From first vaccination through end of study (Day 360 [Month 12]) ]
    A serious adverse event (SAE) is 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.

  11. Percentage of Participants With Medically Attended AEs (MAAEs) [ Time Frame: From first vaccination through end of study (Day 360 [Month 12]) ]
    MAAEs are 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.


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. 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.
  2. Group 1 only: immunologically naïve to dengue, Zika, Yellow Fever (YF), Japanese Encephalitis (JE), West Nile (WN) (based on negative results for detection of anti-DENV, anti-Zika, anti-YF, anti-JE, anti-WN antibodies) as documented by serological testing performed by the trial center outside the scope of this trial (up to 70 days [10 weeks] prior to Day 1 [Month 0]).
  3. Group 2 only: serology consistent with primary infection with either DENV-1 or DENV-3 (defined as detectable neutralizing antibodies against DENV-1 or DENV-3 only, or titers for DENV-1 or DENV-3 ≥4-times higher than titers for the 2 other dengue serotypes) as documented by serological testing performed by the trial center outside the scope of this trial (up to 70 days [10 weeks] prior to Day 1 [Month 0]).

Exclusion Criteria:

  1. Has clinically active significant infection (as assessed by the investigator) or body temperature ≥38°C (100.4°F) within 3 days of the intended date of vaccination.
  2. Has 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 and/or ≥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).
    2. Receipt of parenteral steroids (equivalent to 20 mg/day prednisone ≥12 weeks and/or ≥2 mg/kg body weight/day prednisone ≥2 weeks) within 60 days prior to Day 1 (Month 0).
    3. Administration of immunoglobulins and/or any blood products within 3 months prior to Day 1 (Month 0) or planned administration during the trial.
    4. Receipt of immunostimulants within 60 days prior to Day 1 (Month 0).
    5. Immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within 6 months prior to Day 1 (Month 0).
    6. Known Human Immunodeficiency Virus (HIV) infection or HIV-related disease.
    7. Hepatitis C virus infection.
    8. Genetic immunodeficiency.
  4. Has planned vaccination (during the trial conduct) against any non-dengue flavivirus (eg, Zika, YF, JE, WN, tick-borne encephalitis, or Murray-Valley encephalitis).
  5. Planned travel (during the trial conduct) to any area endemic for dengue.
Contacts and Locations
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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): NCT03746015


Locations
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United States, Illinois
Optimal Research
Peoria, Illinois, United States, 61614
United States, Oregon
Oregon Health and Science University
Portland, Oregon, United States, 97239
Sponsors and Collaborators
Takeda
Investigators
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Study Director: Medical Director Clinical Science Takeda
More Information
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Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT03746015    
Other Study ID Numbers: DEN-210
First Posted: November 19, 2018    Key Record Dates
Last Update Posted: February 25, 2022
Last Verified: February 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
URL: https://vivli.org/ourmember/takeda/

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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
Vector Borne Diseases
Infections
Virus Diseases
 Flavivirus Infections
Flaviviridae Infections
RNA Virus Infections
Hemorrhagic Fevers, Viral