| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The main purpose of this study is to evaluate the efficacy of 2 doses of Tetravalent Dengue Vaccine Candidate (TDV) in preventing symptomatic dengue fever of any severity and due to any of the four dengue virus serotypes in 4 to 16 year old participants. |
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| E.1.1.1 | Medical condition in easily understood language |
| Dengue fever is caused by infection with dengue virus, a RNA virus that occurs as 4 recognized serotypes: DENV-1, -2, -3, or -4. These viruses are transmitted from human to human by mosquitoes. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012312 |
| E.1.2 | Term | Dengue fever virus infection |
| E.1.2 | System Organ Class | 100000004862 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the efficacy of 2 doses of TDV in preventing symptomatic dengue fever of any severity and due to any of the 4 dengue virus serotypes in 4-16 year old subjects. |
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| E.2.2 | Secondary objectives of the trial |
Efficacy:
• To assess the efficacy of TDV in preventing symptomatic dengue fever of any severity induced by individual dengue serotypes.
• To assess the efficacy of TDV in preventing symptomatic dengue fever of any severity by dengue exposure status at baseline.
• To assess the efficacy of TDV in preventing hospitalization due to virologically-confirmed dengue fever.
• To assess the efficacy of TDV in preventing severe dengue induced by any dengue serotype.
Safety:
• To describe the safety of TDV.
• To describe the reactogenicity of TDV in a subset of subjects.
Immunogenicity:
• To assess the immunogenicity of TDV in a subset of subjects.
Participation in a booster phase will be offered to ~10,500 participants to receive a booster dose (TDV or placebo) at the end of the initial study (Parts 1-3). Purpose of this booster phase is to explore the impact of a booster dose on efficacy, safety and immunogenicity of TDV. The duration of this booster phase will be ~ 25 months.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. The subject is aged 4 to 16 years, inclusive, at the time of randomization.
2. Individuals 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.
3. The subject and/or the subject’s parent/guardian signs and dates an assent/written informed consent form where applicable, 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.
Inclusion criteria for Booster Phase:
1. Is included in the per-protocol set (PPS) of the trial.
2. Was aged 4 to 11 years at the time of randomization in the study (Day 1 [Month 0]). |
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| E.4 | Principal exclusion criteria |
1. Febrile illness (temperature ≥38°C) or moderate or severe acute illness or infection at the time of randomization.
2. History or any illness that, in the opinion of the Investigator, might interfere with the results of the trial or pose an additional risk to the subject due to participation in the trial, including but not limited to:
a. Known hypersensitivity or allergy to any of the vaccine components.
b. Female subjects (post-menarche) who are pregnant or breastfeeding.
c. Individuals with any serious chronic or progressive disease according to judgment of the Investigator (eg, neoplasm, insulin-dependent diabetes, cardiac, renal or hepatic disease, neurologic or seizure disorder or Guillain-Barré syndrome).
d. Known or suspected impairment/alteration of immune function, including:
i. 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 (Month 0) (use of inhaled, intranasal, or topical corticosteroids is allowed).
ii. 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 (Month 0).
iii. Administration of immunoglobulins and/or any blood products within the 3 months prior to Day 1 (Month 0) or planned administration during the trial.
iv. Receipt of immunostimulants within 60 days prior to Day 1 (Month 0).
v. Immunosuppressive therapy such as anti-cancer chemotherapy or radiation
therapy within 6 months prior to Day 1 (Month 0).
vi. Human Immunodeficiency Virus (HIV) infection or HIV-related disease.
vii. Genetic immunodeficiency.
3. Receipt of any other vaccine within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to Day 1 (Month 0) or planning to receive any vaccine within 28 days after Day 1 (Month 0).
4. Participation in any clinical trial with another investigational product 30 days prior to Day 1 (Month 0) or intent to participate in another clinical trial at any time during the conduct of this trial.
5. Previous participation in any clinical trial of a dengue candidate vaccine, or previous receipt of a dengue vaccine.
6. First degree relatives of individuals involved in trial conduct.
7. 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 (Month 0).
a. Of childbearing potential is defined as status post onset of menarche and not meeting any of the following conditions: bilateral tubal ligation (at least 1 year previously), bilateral oophorectomy (at least 1 year previously) or hysterectomy.
b. Acceptable birth control methods are defined as 1 or more of the following:
i. Hormonal contraceptive (such as oral, injection, transdermal patch, implant, cervical ring).
ii. Barrier (condom with spermicide or diaphragm with spermicide) each and every time during intercourse.
iii. Intrauterine device (IUD).
iv. Monogamous relationship with vasectomized partner (partner must have been vasectomized for at least six months prior to Day 1 [Month 0]). Other contraceptive methods may be considered in agreement with the Sponsor and will be approved by the appropriate ethics committee.
8. Females of childbearing potential who are sexually active, and who refuse to use an acceptable contraceptive method up to 6 weeks post-second vaccination.
9. Deprived of freedom by administrative or court order, or in an emergency setting, or hospitalized involuntarily.
10. Current alcohol abuse or drug addiction that may interfere with the subject’s ability to comply with trial procedures.
11. Identified as an employee of the Investigator or trial center, with direct involvement in the proposed trial or other trials under the direction of that Investigator or trial center.
Exclusion criteria for Booster Phase:
Receipt of any other vaccine within 14 days (for inactivated vaccines) or 28 days (for live vaccines) prior to Day 1b (Month 0b), or planning to receive any vaccine within 28 days after Day 1b (Month 0b).
Participation in any clinical trial with another investigational product at any time during participation in this trial or intent to participate in another clinical trial at any time during the conduct of the booster phase of this trial. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Efficacy
Vaccine efficacy (VE) of 2 doses of TDV in preventing virologically-confirmed dengue fever induced by any dengue serotype occurring from 30 days post-second vaccination (Day 120 [Month 4]) until the end of Part 1, with VE defined as 1 – (λV/λC) (where λV and λC denote the hazard rates for the TDV and placebo arms, respectively). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Time Frame: 30 days post-second vaccination (Day 120) until the end of Part 1 (120 cases of dengue fever are confirmed and minimum duration of subject follow-up of 12 months post-second vaccination) |
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| E.5.2 | Secondary end point(s) |
Efficacy
• VE of 2 doses of TDV in preventing virologically-confirmed dengue fever induced by each dengue serotype from 30 days post-second vaccination (Day 120 [Month 4]) until the end of Part 2.
• VE of 2 doses of TDV in preventing virologically-confirmed dengue fever induced by any dengue serotype from 30 days post-second vaccination (Day 120 [Month 4]) until the end of Part 2 in subjects dengue seronegative at baseline.
• VE of 2 doses of TDV in preventing virologically-confirmed dengue fever induced by any dengue serotype from 30 days post-second vaccination (Day 120 [Month 4]) until the end of Part 2 in subjects dengue seropositive at baseline.
• VE of 2 doses of TDV in preventing hospitalization due to virologically-confirmed dengue fever induced by any dengue serotype from 30 days post-second vaccination (Day 120 [Month 4]) until the end of Part 2.
• VE of 2 doses of TDV in preventing virologically-confirmed severe dengue fever induced by any dengue serotype from 30 days post-second vaccination (Day 120 [Month 4]) until the end of Part 2.
Safety
Subset (post-first and post-second vaccinations):
• Frequency and severity of solicited local (injection site) AEs for 7 days (day of vaccination + 6 subsequent days) and solicited systemic AEs for 14 days (day of vaccination + 13 subsequent days) post-vaccination.
• Percentage of subjects with any unsolicited AEs for 28 days (day of vaccination + 27 subsequent days) post-vaccination.
All subjects:
• Percentage of subjects with serious adverse events (SAEs) during Parts 1 and 2, Part 1 and Part 2 combined.
• Percentage of subjects with fatal SAEs and related SAEs during the first and second half of Part 3.
Immunogenicity
Subset (post-first and post-second vaccinations):
• Seropositivity rate (% of seropositive subjects) for each of the 4 dengue serotypes at pre-vaccination on Day 1 (Month 0), post-first vaccination on Day 30 (Month 1), pre-vaccination on Day 90 (Month 3); post-second vaccination at Day 120 (Month 4), Day 270 (Month 9), Day 450 (Month 15), and then annually up to 3 years.
• Seropositivity rate (% of seropositive subjects) for multiple (any 2, 3 or 4) dengue serotypes at pre-vaccination on Day 1 (Month 0), post-first vaccination on Day 30 (Month 1), pre-vaccination on Day 90 (Month 3); post-second vaccination at Day 120 (Month 4), Day 270 (Month 9), Day 450 (Month 15), and then annually up to 3 years. Note: Seropositivity is defined as a reciprocal neutralizing titer ≥10.
• Geometric mean titers (GMTs) of neutralizing antibodies (microneutralization test [MNT]) for each dengue serotype at pre-vaccination on Day 1 (Month 0), post-first vaccination on Day 30 (Month 1), pre-vaccination on Day 90 (Month 3); post-second vaccination at Day 120 (Month 4), Day 270 (Month 9), Day 450 (Month 15), and then annually up to 3 years.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Multiple time points occurring as stated in Section E.5.2 |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | Yes |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
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| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
| Brazil |
| Colombia |
| Dominican Republic |
| Nicaragua |
| Panama |
| Philippines |
| Sri Lanka |
| Thailand |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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