Immunogenicity and Safety of Tetravalent Dengue Vaccine (TDV) in Adolescents in Non-Endemic Area(s)

• ClinicalTrials.gov Identifier: NCT03341637
• Recruitment Status: Completed
• First Posted: November 14, 2017
• Results First Posted: August 15, 2019
• Last Update Posted: August 15, 2019
• Sponsor: Takeda
• Information provided by (Responsible Party): Takeda

Study Description

Brief Summary:

The purpose of this study was to describe the neutralizing antibody response against each dengue serotype at 1 month post second dose of TDV or placebo in dengue-naive adolescent participants.

Condition or disease	Intervention/treatment	Phase
Dengue	Biological: Tetravalent Dengue Vaccine (TDV); Biological: Placebo	Phase 3

Detailed Description:

The vaccine tested in this study was tetravalent dengue vaccine (TDV). TDV was tested to assess the safety and immunogenicity in healthy adolescents in non-endemic area(s) for dengue.

The study enrolled 400 healthy participants. Participants were randomized in 3:1 ratio to receive:

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

In each trial group, participants received 2-dose schedule of TDV or placebo by subcutaneous injection on Days 1 (Month 0) and 90 (Month 3), but not all participants received both doses (8 subjects discontinued the trial before receiving the second dose).

This multi-center trial was conducted in Mexico. The overall time to participate in this study was 270 days. Participants had multiple visits to the clinic including a final visit at Day 270.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 400 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial to Investigate the Immunogenicity and Safety of Subcutaneous Administration of a Tetravalent Dengue Vaccine Candidate in Healthy Adolescent Subjects in Non-Endemic Area(s) for Dengue
• Actual Study Start Date: December 14, 2017
• Actual Primary Completion Date: January 26, 2019
• Actual Study Completion Date: January 26, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Tetravalent Dengue Vaccine (TDV); TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose)	Biological: Tetravalent Dengue Vaccine (TDV); TDV subcutaneous injection
Placebo Comparator: Placebo; TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).	Biological: Placebo; Normal Saline (0.9% NaCl) subcutaneous injection

Outcome Measures

Primary Outcome Measures :

1. Geometric Mean Titers (GMTs) 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 were measured by microneutralization test 50% [MNT50] for each of the 4 Dengue Serotypes. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity is defined as reciprocal neutralizing titer ≥10.

Secondary Outcome Measures :

1. 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 measured by microneutralization test 50% [MNT50] for each of the 4 Dengue Serotypes. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4. Seropositivity is defined as reciprocal neutralizing titer ≥10.
2. Seropositivity Rates for Each of the 4 Dengue Serotypes [ Time Frame: One month and six months post second dose (Day 120 and Day 270) ]
   Seropositivity rate, defined as the percentage of participants seropositive, was derived from the titers of dengue-neutralizing antibodies. Seropositivity defined as a reciprocal neutralizing titer ≥10. The 4 dengue virus serotypes were DENV-1, DENV-2, DENV-3 and DENV-4.
3. Seropositivity Rates for Multiple (2, 3 or 4) Dengue Serotypes [ Time Frame: One month and six months post second dose (Day 120 and Day 270) ]
   Seropositivity rate, defined as the percentage of participants seropositive, was derived from the titers of dengue-neutralizing antibodies. Seropositivity was defined as a reciprocal neutralizing titer ≥10.
4. Percentage of Participants With Solicited Local (Injection Site) Adverse Events (AEs) (Diary Recorded) Following Each Vaccination by Severity [ Time Frame: Within 7 days after each vaccination ]
   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) (<2.5 cm, mild: 2.5-5 cm, moderate: >5 to <=10 cm, severe: >10 cm) and swelling (edema/induration) (<2.5 cm, mild: 2.5-5 cm, moderate: >5 to <=10 cm, severe: >10 cm).
5. Percentage of Participants With Solicited Systemic Adverse Events (AEs) (Diary Recorded) Following Each Vaccination by Severity [ Time Frame: Within 14 days after each vaccination ]
   Solicited systemic AEs were collected by participants using diary cards within 14 days after vaccination and included fever, headache, tiredness or weakness (asthenia), feeling of discomfort (malaise) and muscle pain (myalgia). Severity scales for headache were none, mild: no interference with daily activity, moderate: interference with daily activity with or without treatment and severe: prevents normal activity with or without treatment. Severity scales for others were none, mild: no interference with daily activity, moderate: interference with daily activity and 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.
6. Percentage of Participants With Any Unsolicited Adverse Events (AEs) Following Each Vaccination [ Time Frame: Within 28 days after each vaccination ]
   An AE is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment.
7. Percentage of Participants With Medically Attended AEs (MAAEs) Throughout the Study [ Time Frame: From first vaccination (Day 1) through end of study (Day 270) ]
   MAAEs were 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.
8. Percentage of Participants With Serious Adverse Events (SAEs) Throughout the Study [ Time Frame: From first vaccination (Day 1) through end of study (Day 270) ]
   An SAE was 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 due to other reasons than the above mentioned criteria.

Eligibility Criteria

• Ages Eligible for Study: 12 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. The participant is aged 12 to 17 years, inclusive;
2. 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.
3. The participant/the participant's legally authorized representative (LAR) signs and dates a written, informed consent/assent 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.
4. Individuals who can comply with trial procedures and are available for the duration of follow-up.

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.
3. Behavioral or cognitive impairment or psychiatric disease that, in the opinion of the Investigator, may interfere with the participant's ability to participate in the trial.
4. Has any history of progressive or severe neurologic disorder, seizure disorder or neuro-inflammatory disease (e.g., Guillain-Barre syndrome).
5. History or any illness that, in the opinion of the Investigator, might interfere with the results of the trial or pose additional risk to the participant due to participation in the trial.

6. Has 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 immune-stimulants within 60 days prior to Day 1 (M0).
   5. Immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within 6 months prior to Day 1 (M0).
   6. Human immunodeficiency virus (HIV) infection or HIV-related disease.
   7. Genetic immunodeficiency.
7. Has abnormalities of splenic or thymic function.
8. Has a known bleeding diathesis, or any condition that may be associated with a prolonged bleeding.
9. Has any serious chronic or progressive disease according to judgment of the Investigator (e.g., neoplasm, insulin dependent diabetes, cardiac, renal or hepatic disease).
10. Has body mass index (BMI) greater than or equal to 35 kg/m^2 (= weight in kg/[height in square meters]).
11. Individuals participating in any clinical trial with another investigational product 30 days prior to Day 1 (M0) or intent to participate in another clinical trial at any time during the conduct of this trial.
12. Has received any other vaccine within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to enrollment in this trial or who are planning to receive any vaccine within 28 days of trial vaccine administration.
13. Individuals involved in the trial conduct or their first degree relatives.
14. Has history of substance or alcohol abuse within the past 2 years.
15. Female participants who are pregnant or breastfeeding.
16. 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 (M0).
17. Females of childbearing potential who are sexually active, and who refuse to use an acceptable contraceptive method up to 6 weeks after the last dose of trial vaccine. In addition, they must be advised not to donate ova during this period.
18. Any positive or indeterminate pregnancy test.
19. Previous and planned vaccination (during the trial conduct), against any flaviviruses including dengue, yellow fever (YF), Japanese encephalitis (JE) viruses or tick-borne encephalitis.
20. Previous participation in any clinical trial of a dengue or other flavivirus (eg, West Nile [WN] virus) candidate vaccine, except for participants who received placebo in those trials.
21. Participants with documented or suspected disease caused by a flavivirus such as dengue, Zika, YF, JE, WN fever, tick-borne encephalitis or Murray Valley encephalitis.

Contacts and Locations

Locations

Mexico

Biodextra, S.A. de C.V.

Ciudad de Mexico, Mexico, 09360

Instituto Nacional de Pediatria (INP)

Mexico City, Mexico, 04530

Hospital Infantil de Mexico Federico Gomez

Mexico City, Mexico, 06720

Mexico Centre for Clinical Research

Mexico City, Mexico, ZC 03100

Centro de Atencion E Investigacion Medica (CAIMED) Mexico DF

Mexico City, Mexico

Sponsors and Collaborators

Takeda

Investigators

• Study Director: Medical Director Clinical Science; Takeda

  Study Documents (Full-Text)

Documents provided by Takeda:

Study Protocol  [PDF] March 9, 2019

Statistical Analysis Plan  [PDF] January 30, 2019

More Information

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT03341637
• Other Study ID Numbers: DEN-315; U1111-1192-7827 ( Other Identifier: World Health Organization ); RNEC-2017-DEN-315 ( Registry Identifier: Mexico ); 2018-003980-77 ( EudraCT Number )
• First Posted: November 14, 2017
• Results First Posted: August 15, 2019
• Last Update Posted: August 15, 2019
• Last Verified: July 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Takeda makes patient-level, de-identified data sets and associated documents available after applicable marketing approvals and commercial availability have been received, an opportunity for the primary publication of the research has been allowed, and other criteria have been met as set forth in Takeda's Data Sharing Policy (see www.TakedaClinicalTrials.com/Approach for details). To obtain access, researchers must submit a legitimate academic research proposal for adjudication by an independent review panel, who will review the scientific merit of the research and the requestor's qualifications and conflict of interest that can result in potential bias. Once approved, qualified researchers who sign a data sharing agreement are provided access to these data in a secure research environment.

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

Keywords provided by Takeda:

Drug Therapy

Additional relevant MeSH terms:

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