Lot-to-lot Consistency of 3 Lots of Tetravalent Dengue Vaccine (TDV) in Non-endemic Country(Ies) for Dengue

• ClinicalTrials.gov Identifier: NCT03423173
• Recruitment Status: Completed
• First Posted: February 6, 2018
• Results First Posted: October 20, 2020
• Last Update Posted: October 20, 2020
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

Study Description

Brief Summary:

The purpose of this study is to investigate lot-to-lot consistency in terms of equivalence of the immune responses induced by 3 consecutive TDV lots in healthy participants aged 18 to 60 years in non-endemic country(ies) for dengue.

Condition or disease	Intervention/treatment	Phase
Dengue Fever	Biological: TAK-003; Biological: Placebo	Phase 3

Detailed Description:

The vaccine tested in this study is Takeda's Tetravalent Dengue Vaccine Candidate (TDV). The primary objective of this trial is to investigate lot-to-lot consistency in terms of equivalence of the immune responses induced by 3 consecutive lots of TDV in healthy participants in non-endemic country(ies) for dengue.

The study will enroll approximately 924 healthy participants. Participants will be randomized in 2:2:2:1 to one of 4 trial groups to receive TDV (Lots 1, 2 or 3) or placebo:

• TDV 0.5 mL subcutaneous injection OR
• Placebo normal saline solution (0.9% NaCl) for injection.

In each trial group, all participants will receive 2 doses of TDV or placebo by subcutaneous injection on Days 1 (Month 0) and 90 (Month 3). Immunogenicity will be assessed in participants included in the immunogenicity subset (TDV groups: 176 participants each and placebo group: 88 participants) and safety will be assessed in all participants in each group.

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 923 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: A double-blind study.
• Primary Purpose: Prevention
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Demonstrate Lot-to-Lot Consistency of 3 Lots of a Tetravalent Dengue Vaccine Candidate in Healthy Adults in Non-Endemic Country(Ies) for Dengue
• Actual Study Start Date: February 12, 2018
• Actual Primary Completion Date: August 3, 2018
• Actual Study Completion Date: January 14, 2019

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; TDV placebo matching injection, subcutaneously (SC) once on Day 1, and Day 90.	Biological: Placebo; TDV Placebo-matching normal saline (0.9% NaCl) subcutaneous injection
Experimental: TDV Lot 1; Participants were administered TDV lot 1, 0.5 ml (each TDV 0.5 mL dose contained TDV-1, TDV-2, TDV-3, and TDV-4), SC injection, once on Day 1, and Day 90.	Biological: TAK-003; TDV subcutaneous injection; Other Name: TDV
Experimental: TDV Lot 2; Participants were administered TDV lot 2, 0.5 ml (each TDV 0.5 mL dose contained TDV-1, TDV-2, TDV-3, and TDV-4), SC injection, once on Day 1, and Day 90.	Biological: TAK-003; TDV subcutaneous injection; Other Name: TDV
Experimental: TDV Lot 3; Participants were administered TDV lot 3, 0.5 ml (each TDV 0.5 mL dose contained TDV-1, TDV-2, TDV-3, and TDV-4), SC injection once on Day 1, and Day 90.	Biological: TAK-003; TDV subcutaneous injection; Other Name: TDV

Outcome Measures

Primary Outcome Measures :

1. Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Day 120 in the Immunogenicity Subset [ Time Frame: 1 month post second dose (Day 120) ]
   GMTs of neutralizing antibodies for each of the 4 Dengue Serotypes was measured by microneutralization test 50% [MNT50]. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4.

Secondary Outcome Measures :

1. Percentage of Participants Who Are Seropositive for Each of the 4 Dengue Serotypes at Days 120 and 270 in the Immunogenicity Subset [ Time Frame: 1 month post second dose (Day 120) and 6 months post second dose (Day 270) ]
   Seropositivity was defined as a reciprocal neutralizing titer ≥ 10. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4.
2. GMTs of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Day 270 in the Immunogenicity Subset [ Time Frame: 6 months post second dose (Day 270) ]
   GMTs of neutralizing antibodies for each of the 4 Dengue Serotypes was measured by microneutralization test 50% [MNT50]. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4.
3. Percentage of Participants With Solicited Local (Injection Site) Adverse Events (AEs) by Severity After Each Vaccination [ Time Frame: Within 7 Days of each Vaccination (day of vaccination + 6 days) ]
   Solicited local AEs (at injection site) were collected by participants using diary cards within 7 days after vaccination and included pain (none, mild: no interference with daily activity, moderate: interference with daily activity with or without treatment and severe: prevents daily activity with or without treatment), redness (erythema) (<25 mm, mild: >25 - ≤50 mm, moderate: >50 - ≤100 mm, severe: >100 mm) and swelling (edema/induration) (<25 mm, mild: >25 - ≤50 mm, moderate: >50 - ≤100 mm, severe: >100 mm ). The percentages were rounded off to the first decimal place.
4. Percentage of Participants With Solicited Systemic Adverse Events (AEs) by Severity After Each Vaccination [ Time Frame: Within 14 Days of each Vaccination (day of vaccination + 13 days) ]
   Solicited systemic AEs include fever, headache, asthenia, malaise and myalgia that occurred within 14 days after each vaccination. Solicited systemic AEs (headache, asthenia, malaise and myalgia) was graded from 0 to 3 by severity; where 0=None, 1=Mild: No interference with daily activity, 2=Moderate: Interference with daily activity, 3=Severe: Prevents daily activity; A systemic AE of fever (defined as ≥38°C or ≥100.4°F) was derived from a daily temperature reading recorded within 14 days after vaccination. 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.
5. Percentage of Participants With Any Unsolicited Adverse Events (AEs) After Each Vaccination [ Time Frame: Within 28 days (day of vaccination + 27 days) after each vaccination ]
   An AE was defined as any untoward medical occurrence in a clinical investigation participant administered a trial vaccine; it does not necessarily have to have a causal relationship with trial vaccine administration.
6. Percentage of Participants With Serious Adverse Events (SAEs) [ Time Frame: From the first vaccination on Day 1 until the end of the trial (Day 270) ]
   An SAE was 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, is an important medical event that may require intervention to prevent any of the above mentioned criteria and/or may expose the participant to danger, even though the event is not immediately life threatening or fatal or does not result in hospitalization. The percentages were rounded off to the first decimal place.
7. Percentage of Participants With Medically Attended Adverse Events (MAAEs) [ Time Frame: From the first vaccination on Day 1 until the end of the trial (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. The percentages were rounded off to the first decimal place.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

1. Is 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. Signs and dates 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. Has an elevated oral temperature (≥38°C or 100.4°F) within 3 days of the intended date of vaccination.
2. Known hypersensitivity or allergy to any of the vaccine components (including excipients of the investigational vaccine or placebo).
3. Has any history of progressive or severe neurologic disorder, seizure disorder or neuro-inflammatory disease (e.g., Guillain-Barré syndrome).

4. 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 Day 1 (M0) (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 Day 1 (M0).
   3. Administration of immunoglobulins and/or any blood products within the 3 months prior to Day 1 (M0) or planned administration during the trial.
   4. Receipt of immunostimulants within 60 days prior to Day 1 (M0).
   5. Hepatitis C virus infection.
   6. Genetic immunodeficiency.
5. Has abnormalities of splenic or thymic function.
6. Has a known bleeding diathesis, or any condition that may be associated with a prolonged bleeding time.
7. Has any serious chronic or progressive disease according to judgment of the Investigator (e.g., neoplasm, insulin dependent diabetes, cardiac, renal or hepatic disease).
8. Has body mass index (BMI) greater than or equal to 35 kg/m^2 (= weight in kg/[height in meters^2]).
9. Has history of substance or alcohol abuse within the past 2 years.
10. Had previous and planned vaccination (during the trial conduct) against any flavivirus including dengue, yellow fever (YF), Japanese encephalitis (JE) viruses or tick-borne encephalitis.
11. Has a current or previous infection with a flavivirus such as dengue, Zika, YF, JE, West Nile (WN) fever, tick-borne encephalitis or Murray Valley encephalitis and participants with a history of prolonged (≥1 year) habitation in a dengue endemic area.

Contacts and Locations

Locations

United States, Alabama

Optimal Research

Huntsville, Alabama, United States, 35802

United States, California

Anaheim Clinical Trials, LLC

Anaheim, California, United States, 92805

United States, Idaho

Advanced Clinical Research

Boise, Idaho, United States, 83704

United States, Illinois

Optimal Research

Peoria, Illinois, United States, 61614

United States, Iowa

Synexus Limited- Council Bluffs

Council Bluffs, Iowa, United States, 51503

United States, Kansas

Heartland Research Associates LLC - Augusta

Augusta, Kansas, United States, 67010

Heartland Research Associates LLC

Park City, Kansas, United States, 67219

United States, Maryland

Optimal Research

Rockville, Maryland, United States, 20850

United States, Minnesota

Synexus Limited - Minneapolis

Edina, Minnesota, United States, 55435

United States, Missouri

Synexus Limited - St. Louis

Saint Louis, Missouri, United States, 63141

United States, Nevada

Clinical Research Center of Nevada

Las Vegas, Nevada, United States, 89104

United States, Ohio

Synexus Limited - Columbus

Columbus, Ohio, United States, 43212

United States, Utah

Advanced Clinical Research

Salt Lake City, Utah, United States, 84123

Advanced Clinical Research

West Jordan, Utah, United States, 84088

Sponsors and Collaborators

Takeda

Investigators

• Study Director: Medical Director Clinical Science; Takeda

  Study Documents (Full-Text)

Documents provided by Takeda:

Study Protocol  [PDF] October 29, 2018

Statistical Analysis Plan  [PDF] January 31, 2019

More Information

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT03423173
• Other Study ID Numbers: DEN-304
• First Posted: February 6, 2018
• Results First Posted: October 20, 2020
• Last Update Posted: October 20, 2020
• Last Verified: October 2020

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/

• 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:

Dengue; Arbovirus Infections; Virus Diseases; Flavivirus Infections; Flaviviridae Infections; RNA Virus Infections; Hemorrhagic Fevers, Viral