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

Phase 3

Completed

• Conditions: Dengue
• Interventions: Biological: Tetravalent Dengue Vaccine (TDV); Biological: Placebo

• Registration Number: NCT03341637
• Lead Sponsor: Takeda

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.

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 Timeline

• Study First Submitted: 2017-11-09
• Study First Submitted QC: 2017-11-09
• Study First Posted: 2017-11-14
• Study Start: 2017-12-14
• Primary Completion: 2019-01-26
• Study Completion: 2019-01-26
• Status Verified: 2019-07
• Results First Submitted: 2019-07-23
• Results First Submitted QC: 2019-07-23
• Last Update Submitted: 2019-07-23
• Results First Posted: 2019-08-15
• Last Update Posted: 2019-08-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 400

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.

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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.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Tetravalent Dengue Vaccine (TDV)	Tetravalent Dengue Vaccine (TDV)	TDV 0.5 mL, injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose)
Placebo	Placebo	TDV placebo-matching 0.5 mL injection, subcutaneously, once on Day 0 (first dose) and Day 90 (second dose).

Primary Outcome Measures

Name	Time	Method
Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Day 120	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

Name	Time	Method
Percentage of Participants With Solicited Systemic Adverse Events (AEs) (Diary Recorded) Following Each Vaccination by Severity	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.
Percentage of Participants With Solicited Local (Injection Site) Adverse Events (AEs) (Diary Recorded) Following Each Vaccination by Severity	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).
Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the 4 Dengue Serotypes at Day 270	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.
Seropositivity Rates for Each of the 4 Dengue Serotypes	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.
Seropositivity Rates for Multiple (2, 3 or 4) Dengue Serotypes	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.
Percentage of Participants With Any Unsolicited Adverse Events (AEs) Following Each Vaccination	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.
Percentage of Participants With Medically Attended AEs (MAAEs) Throughout the Study	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.
Percentage of Participants With Serious Adverse Events (SAEs) Throughout the Study	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.

Trial Locations

Locations (5)

Instituto Nacional de Pediatria (INP); 🇲🇽 Mexico City, Mexico

Mexico Centre for Clinical Research; 🇲🇽 Mexico City, Mexico

Centro de Atencion E Investigacion Medica (CAIMED) Mexico DF; 🇲🇽 Mexico City, Mexico

Hospital Infantil de Mexico Federico Gomez; 🇲🇽 Mexico City, Mexico

Biodextra, S.A. de C.V.; 🇲🇽 Ciudad de Mexico, Mexico