Immunogenicity and Safety of Tetravalent Dengue Vaccine (TDV) at the End of Shelf Life in Healthy Adults

• ClinicalTrials.gov Identifier: NCT03771963
• Recruitment Status: Completed
• First Posted: December 11, 2018
• Results First Posted: June 7, 2021
• Last Update Posted: June 7, 2021
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

Tracking Information

• First Submitted Date: December 10, 2018
• First Posted Date: December 11, 2018
• Results First Submitted Date: May 11, 2021
• Results First Posted Date: June 7, 2021
• Last Update Posted Date: June 7, 2021
• Actual Study Start Date: March 28, 2019
• Actual Primary Completion Date: October 14, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 11, 2021)

Geometric Mean Titers (GMT) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Day 120 [ Time Frame: One month post second dose (Day 120) ]

GMTs of neutralizing antibodies for each of the 4 dengue serotypes were measured by microneutralization test 50% [MNT50]. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3, and DENV-4.

Original Primary Outcome Measures (submitted: December 10, 2018)

Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 120 (Month 4) [ Time Frame: Day 120 (Month 4) ]

GMTs of neutralizing antibodies for each of the 4 dengue serotypes will be measured by microneutralization test 50% (MNT50).

Current Secondary Outcome Measures (submitted: May 11, 2021)

• Seropositivity Rates for Each of the 4 Dengue Serotypes at Days 120 and 270 [ Time Frame: One month and six months post second dose (Days 120 and 270) ]
  Seropositivity rate was defined as the percentage of participants being seropositive, derived from titers of dengue-neutralizing antibodies. Seropositivity was defined as a reciprocal neutralizing titer ≥10 (for each serotype). Seropositivity rates were assessed for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4.
• Seropositivity Rates for Multiple (2, 3, or 4) Dengue Serotypes at Days 120 and 270 [ Time Frame: One month and six months post second dose (Days 120 and 270) ]
  Seropositivity rate was defined as the percentage of participants being seropositive, derived from titers of dengue-neutralizing antibodies. Seropositivity was defined as a reciprocal neutralizing titer ≥10. The dengue virus serotypes are DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity for multiple dengue serotypes was summarized in the following categories: tetravalent and at least trivalent.
• Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Day 270 [ Time Frame: Six months post second dose (Day 270) ]
  GMTs of neutralizing antibodies were assessed for the four dengue serotypes: DENV-1, DENV-2, DENV-3, and DENV-4, by MNT50.
• Percentage of Participants With Solicited Local (Injection Site) Reactions Following Each Vaccination by Severity [ Time Frame: Up to 7 days (Day of vaccination + 6 subsequent days) after each of the vaccination ]
  Solicited local adverse events (AEs) [at injection site] were collected by participants using diary cards within 7 days after each vaccination and included 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)]. The percentages were rounded off to the first decimal place. Only categories with at least 1 participant are reported.
• Percentage of Participants With Solicited Systemic Adverse Events Following Each Vaccination by Severity [ Time Frame: Up to 14 days (Day of vaccination + 13 subsequent days) after each vaccination ]
  Solicited systemic AEs were collected by participants using diary cards within 14 days after each vaccination and included fever, headache, asthenia, malaise and myalgia. Severity grades were: 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). Fever is defined as body temperature greater than or equal to 38°C (100.4°F). Fever was excluded from the overall count as no severity grading was applied for it. The percentages were rounded off to the first decimal place. Only categories with at least 1 participant are reported.
• Percentage of Participants With Any Unsolicited Adverse Events Following Each Vaccination [ Time Frame: Up to 28 days after each vaccination (Day of vaccination + 27 subsequent days) ]
  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.
• Percentage of Participants With Serious Adverse Events (SAEs) [ Time Frame: From first vaccination (Day 1) through end of study (Day 270) ]
  An SAE is defined as any untoward medical occurrence that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability / incapacity, leads to a congenital anomaly / birth defect in the offspring of a participant, or is an important medical event which may require intervention to prevent the items listed above or may expose the participant to danger, even though the event is not immediately life threatening or fatal or does not result in hospitalization.
• Percentage of Participants With Medically Attended Adverse Events (MAAEs) [ Time Frame: From first vaccination (Day 1) through end of study (Day 270) ]
  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.

Original Secondary Outcome Measures (submitted: December 10, 2018)

• Percentage of Participants with Seropositivity for Each of the Four Dengue Serotypes at Day 120 (Month 4) and Day 270 (Month 9) [ Time Frame: Days 120 (Month 4) and 270 (Month 9) ]
  Seropositivity is defined as a reciprocal neutralizing titer ≥10.
• Percentage of Participants with Seropositivity for Each of the Multiple (2, 3 or 4) Dengue Serotypes at Day 120 (Month 4) and Day 270 (Month 9) [ Time Frame: Days 120 (Month 4) and 270 (Month 9) ]
  Seropositivity is defined as a reciprocal neutralizing titer ≥10.
• Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the Four Dengue Serotypes at Day 270 (Month 9) [ Time Frame: Day 270 (Month 9) ]
  GMTs of neutralizing antibodies for each of the 4 dengue serotypes will be measured by MNT50.
• Percentage of Participants with Solicited Local (Injection Site) Reactions Following Vaccination by Severity [ Time Frame: Within 7 days after each of the vaccination given on Day 1 (Month 0) or 90 (Month 3) ]
  Solicited local Adverse Events (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)].
• Percentage of Participants with Solicited Systemic Adverse Events Following Vaccination by Severity [ Time Frame: Within 14 days after each 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 were: 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). Fever is defined as body temperature greater than or equal to 38°C (100.4°F).
• Percentage of Participants with any Unsolicited Adverse Events (AEs) Following Vaccination [ Time Frame: Within 28 days after each 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.
• Percentage of Participants with Serious Adverse Events (SAEs) [ Time Frame: From first vaccination (Day 1) through end of study (Day 270 [Month 9]) ]
  A SAE is 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 which may require intervention to prevent the items listed above or may expose the participant to danger.
• Percentage of Participants With Medically Attended AEs (MAAEs) [ Time Frame: From first vaccination (Day 1) through end of study (Day 270 [Month 9]) ]
  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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Immunogenicity and Safety of Tetravalent Dengue Vaccine (TDV) at the End of Shelf Life in Healthy Adults
• Official Title: An Open-Label, Phase 3 Trial to Investigate the Immunogenicity and Safety of Tetravalent Dengue Vaccine Candidate (TDV) at the End of Shelf Life in Healthy Adults in Non-Endemic Country(Ies) for Dengue
• Brief Summary: The purpose of this study is to evaluate the safety and immune response of a naturally aged lot of tetravalent dengue vaccine (TDV) in healthy participants, aged 18 to 60 years, in non-endemic country(ies) for dengue.

Detailed Description

The vaccine being tested in this study is tetravalent dengue vaccine (TDV). The primary objective of this study is to evaluate the immune response and safety of a naturally aged (>12 months stored at 2°C to 8°C) lot of TDV in a healthy adult population in country(ies) non-endemic for dengue. The assessment of a naturally aged lot of TDV in this clinical trial will provide an important contribution to data on TDV stability throughout the shelf life of the product.

The study will enroll approximately 200 participants. Participants will be enrolled to the one treatment group:

Tetravalent Dengue Vaccine (TDV)

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

This multi-center trial will be conducted in the United States. The overall time to participate in this study is 9 months. Participants will make multiple visits to the clinic including a final visit at Day 270 (Month 9).

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Prevention
• Condition: Dengue Fever

Intervention

Biological: Tetravalent Dengue Vaccine (TDV)

TDV SC injection.

Study Arms

Experimental: Tetravalent Dengue Vaccine (TDV)

TDV 0.5 mL, injection, subcutaneously (SC), once on Day 1 (first dose) and Day 90 (second dose).

Intervention: Biological: Tetravalent Dengue Vaccine (TDV)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 10, 2018): 200
• Original Estimated Enrollment: Same as current
• Actual Study Completion Date: March 13, 2020
• Actual Primary Completion Date: October 14, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Participants who are in good health at the time of entry into the trial as determined by medical history, physical examination (including vital signs), and the clinical judgment of the investigator.
2. Participants who sign and date a written informed consent form 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.

Exclusion Criteria:

1. Participants with a clinically significant active infection (as assessed by the investigator) or body temperature ≥38°C (≥100.4°F) within 3 days of the intended date of vaccine administration

2. 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 the 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.
3. With Body Mass Index (BMI) greater than or equal to 35 kg/m^2(=weight in kg/height in meters^2).
4. Participants who have known hypersensitivity or allergy to any of the vaccine components.
5. Previous and planned vaccination (during the trial conduct), against any flavivirus including dengue, Yellow Fever (YF), Japanese Encephalitis (JE) viruses or tick-borne encephalitis.
6. Previous participation in any clinical trial of a dengue or other flavivirus (e.g., West Nile [WN] virus) candidate vaccine, except for participants who received placebo in those trials.
7. With a current or previous infection with a flavivirus such as dengue, Zika, YF, JE, WN fever, tick-borne encephalitis or Murray Valley encephalitis and participants with a history of prolonged (≥1 year) habitation in a dengue endemic area.
8. Participants with any history of progressive or severe neurologic disorder, seizure disorder or neuro-inflammatory disease (e.g., Guillain-Barré syndrome).
9. Participants with history of substance or alcohol abuse within the past 2 years.
10. Participants who have any serious chronic or progressive disease according to judgment of the Investigator (e.g., neoplasm, insulin dependent diabetes, cardiac, renal or hepatic disease).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03771963
• Other Study ID Numbers: DEN-307; U1111-1222-2812 ( Registry Identifier: WHO )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

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
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Informed Consent Form (ICF)
• Supporting Materials: 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/

• Current Responsible Party: Takeda
• Original Responsible Party: Same as current
• Current Study Sponsor: Takeda
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Study Director; Takeda

• PRS Account: Takeda
• Verification Date: May 2021