Efficacy, Safety and Immunogenicity of Takeda's Tetravalent Dengue Vaccine (TDV) in Healthy Children

Study Overview
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Brief Summary
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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.

Detailed Description
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The vaccine being tested in this study is Takeda's Tetravalent Dengue Vaccine Candidate (TDV). TDV is being tested to protect people against dengue fever and to look at long-term safety results. This study will look at the success rate of TDV in preventing dengue fever (vaccine efficacy) and long-term side effects of the vaccine. The study will be conducted in 5 parts. Part 1 will evaluate vaccine efficacy (VE) and will last a minimum of 15 months. Part 2 will be for an additional 6 months to evaluate VE. Part 3 will evaluate long-term safety by following participants for side effects and will last an additional 3 years. Part 4 will evaluate safety for 13 months post-booster vaccination. Part 5 will be the long-term safety follow-up for 1 year after completion of Part 4. Participants may be enrolled into a dry-run to commence and test febrile surveillance methodology; this dry-run part may be up to 10 months prior to receiving study injection, however, will not be applicable to all trials sites or participants. Approximately 20,100 participants will be enrolled into the study and randomly assigned (by chance) to one of the two treatment groups-which will remain undisclosed to the participants and study doctors during the study (unless there is an urgent medical need): TDV 0.5 mL subcutaneous injection Placebo (dummy inactive subcutaneous injection) - this is a solution that looks like the study drug but has no active ingredient All participants will receive a single injection of TDV or placebo on Day 1, Day 90. Participation in a booster phase will be offered to approximately 10,500 participants to receive (TDV or placebo) on Day 1b (Day 1 in booster phase). A subset of participants will be asked to record any local symptoms at the injection site (Pain, Erythema and Swelling) in a diary card for 7 days after each injection. The same subset of participants will also be asked to record any systemic symptoms (child <6 years: fever, irritability/fussiness, drowsiness, loss of appetite and child ≥6 years: fever, headache, asthenia, malaise and myalgia) in a diary card for 14 days after each injection. This multi-center trial will be conducted worldwide. The overall time to participate in this study is approximately 7 years excluding the dry-run. Participants will make multiple visits to the clinic and will be contacted at least every week for the entire study duration.

Official Title
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Phase III, Double-Blind, Randomized, Placebo-Controlled Trial to Investigate the Efficacy, Safety and Immunogenicity of a Tetravalent Dengue Vaccine (TDV) Administered Subcutaneously in Healthy Children Aged 4 - 16 Years Old

Conditions
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Healthy Volunteers

Intervention / Treatment
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* Drug: Placebo
* Biological: Tetravalent Dengue Vaccine (TDV)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is aged 4 to 16 years, inclusive, at the time of randomization. Is 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. The participant and/or the participant'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. Can comply with trial procedures and are available for the duration of follow-up. Inclusion criteria for Booster Phase: Is included in the per-protocol set (PPS) of the trial. Was aged 4 to 11 years at the time of randomization in the study (Day 1 [Month 0]). Exclusion Criteria: Has febrile illness (temperature ≥38°C) or moderate or severe acute illness or infection at the time of randomization. Has history of 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 participant due to participation in the trial. Has received 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). Has participated 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. Has previously participated in any clinical trial of a dengue candidate vaccine, or previous receipt of a dengue vaccine. Is first degree relative of individuals involved in trial conduct. 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). Females of childbearing potential who are sexually active, and who refuse to use an acceptable contraceptive method up to 6 weeks post-second vaccination. Deprived of freedom by administrative or court order, or in an emergency setting, or hospitalized involuntarily. Current alcohol abuse or drug addiction that may interfere with the participant's ability to comply with trial procedures. 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.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo-matching TDV, 0.5mL, subcutaneous (SC) injection on Day 1 (Month 0) and Day 90 (Month 3). Participants eligible for Booster Phase received placebo matching TDV, SC injection, based on the randomization on Day 1 (Month 0). | Drug: Placebo<br>* TDV placebo-matching SC injection.<br>|
| Experimental: Tetravalent Dengue Vaccine (TDV) 0.5 mL<br>TDV, 0.5mL, subcutaneous (SC) injection on Day 1 (Month 0) and Day 90 (Month 3). Participants eligible for Booster Phase received TDV, SC injection, based on the randomization on Day 1 (Month 0). | Biological: Tetravalent Dengue Vaccine (TDV)<br>* TDV SC injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vaccine Efficacy (VE) of Two Doses of Tetravalent Dengue Vaccine Candidate (TDV) in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype | The Vaccine Efficacy is defined as 1 - (λv/λc), where λv and λc denote the hazard rates for the TDV and placebo arms, respectively. A virologically-confirmed dengue case is defined as febrile illness (defined as temperature ≥38°C on any 2 of 3 consecutive days) or illness clinically suspected to be dengue by the Investigator with a positive serotype-specific reverse transcriptase polymerase chain reaction (RT-PCR). The primary endpoint of vaccine efficacy was assessed using the number of confirmed dengue cases that occurred during Part 1. | 30 days post-second vaccination (Day 120) until the end of Part 1 (120 cases of dengue fever are confirmed and minimum duration of participant follow-up of 12 months post-second vaccination) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Each Dengue Serotype | VE is defined as 1 - (λv/λc), where λv and λc denote the hazard rates for the TDV and placebo arms, respectively. A virologically-confirmed dengue case is defined as febrile illness (defined as temperature ≥38°C on any 2 of 3 consecutive days) or illness clinically suspected to be dengue by the Investigator with a positive serotype-specific reverse transcriptase polymerase chain reaction (RT-PCR). | From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months) | 
| VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype in Participants Dengue Seronegative at Baseline | VE is defined as 1 - (λv/λc), where λv and λc denote the hazard rates for the TDV and placebo arms, respectively. A virologically-confirmed dengue case is defined as febrile illness (defined as temperature ≥38°C on any 2 of 3 consecutive days) or illness clinically suspected to be dengue by the Investigator with a positive serotype-specific reverse transcriptase polymerase chain reaction (RT-PCR). | From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months) | 
| VE of Two Doses of TDV in Preventing Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype in Participants Dengue Seropositive at Baseline | VE is defined as 1 - (λv/λC), where λv and λc denote the hazard rates for the TDV and placebo arms, respectively. A virologically-confirmed dengue case is defined as febrile illness (defined as temperature ≥38°C on any 2 of 3 consecutive days) or illness clinically suspected to be dengue by the Investigator with a positive serotype-specific reverse transcriptase polymerase chain reaction (RT-PCR). | From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months) | 
| VE of Two Doses of TDV in Preventing Hospitalization Due to Virologically-Confirmed Dengue Fever Induced by Any Dengue Serotype | VE is defined as 1 - (λv/λc), where λv and λc denote the hazard rates for the TDV and placebo arms, respectively. A virologically-confirmed dengue case is defined as febrile illness (defined as temperature ≥38°C on any 2 of 3 consecutive days) or illness clinically suspected to be dengue by the Investigator with a positive serotype-specific reverse transcriptase polymerase chain reaction (RT-PCR). | From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months) | 
| VE of Two Doses of TDV in Preventing Virologically-Confirmed Severe Dengue Fever Induced by Any Dengue Serotype | VE is defined as 1 - (λv/λc), where λv and λc denote the hazard rates for the TDV and placebo arms, respectively. A virologically-confirmed dengue case is defined as febrile illness (defined as temperature ≥38°C on any 2 of 3 consecutive days) or illness clinically suspected to be dengue by the Investigator with a positive serotype-specific reverse transcriptase polymerase chain reaction (RT-PCR). | From 30 days post-second vaccination (Day 120) until the end of Part 2 (up to 21 months) | 
| Percentage of Participants With Solicited Local Injection Site Adverse Events (AEs) by Severity in the Safety Subset | Solicited local AEs at injection site are defined as pain, erythema and swelling that occurred within 7 days after each vaccination. | Days 1 through 7 after each vaccination | 
| Percentage of Participants With Solicited Systemic Adverse Events (AEs) by Severity in the Safety Subset | Solicited systemic AEs in children (< 6 years) are defined as fever, irritability/fussiness, drowsiness and loss of appetite that occurred within 14 days after each vaccination. Solicited systemic AEs in children (≥ 6 years) are defined as fever, headache, asthenia, malaise and myalgia that occurred within 14 days after each vaccination. | Days 1 through 14 after each vaccination | 
| Severity of Solicited Systemic Adverse Events (AEs) in the Safety Subset | Solicited systemic AEs in children (< 6 years) are defined as fever, irritability/fussiness, drowsiness and loss of appetite that occurred within 14 days after each vaccination. Solicited systemic AEs in children (≥ 6 years) are defined as fever, headache, asthenia, malaise and myalgia that occurred within 14 days after each vaccination. | Days 1 through 14 after each vaccination | 
| Percentage of Participants With Any Unsolicited Adverse Events (AEs) in the Safety Subset | An AE is 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. Unsolicited AEs are any AEs that are not solicited local or systemic AEs, as defined by this study. | Days 1 through 28 after each vaccination | 
| Percentage of Participants With Serious Adverse Events (SAEs) During Parts 1 and 2 | A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose 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. | From Day 1 until the end of Parts 1 and 2 (approximately 21 months) | 
| Percentage of Participants With Fatal SAEs and SAEs Related to Study Drug During the First and Second Half of Part 3 | A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose 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. | First and Second half (18 months each) of Part 3 (up to 3 years, beginning at Month 22) | 
| Percentage of Participants With a Seropositive Response for Each of the Four Dengue Serotypes in the Immunogenicity Subset | Seropositive response is defined as a reciprocal neutralizing titer ≥ 10. The four DENV serotypes are DEN-1, DEN-2, DEN-3 and DEN-4. | Prevaccination on Day 1, post-first vaccination on Month 1, pre-vaccination on Month 3; post-second vaccination at Months 4, 9 and 15, and then annually (up to 3 years) | 
| Percentage of Participants With a Seropositive Response for Multiple Dengue Serotypes in the Immunogenicity Subset | Seropositive response is defined as a reciprocal neutralizing titer ≥ 10. The four DENV serotypes are DEN-1, DEN-2, DEN-3 and DEN-4. | Prevaccination on Day 1, post-first vaccination on Month 1, pre-vaccination on Month 3; post-second vaccination at Months 4, 9 and 15, and then annually (up to 3 years) | 
| Geometric Mean Titers (GMTs) of Neutralizing Antibodies for Each of the Four Dengue Serotypes in the Immunogenicity Subset | GMTs of neutralizing antibodies will be measured via microneutralization test 50% (MNT50). The four DENV serotypes are DEN-1, DEN-2, DEN-3 and DEN-4. | Prevaccination on Day 1, post-first vaccination on Month 1, pre-vaccination on Month 3; post-second vaccination at Months 4, 9 and 15, and then annually (up to 3 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy