Safety and Immunogenicity of Three Formulations of Takeda's Tetravalent Dengue Vaccine Candidate (TDV)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the equivalence of the lyophilized formulation of Takeda's Tetravalent Dengue Vaccine Candidate (TDV) compared with the liquid formulation of TDV.

Detailed Description
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The vaccine being tested in this study is Takeda's Tetravalent Dengue Vaccine Candidate (TDV). This study is designed to determine whether the lyophilized formulation provides equivalent safety and immunogenicity as the original liquid formulation. An exploratory analysis has been added for the purpose of understanding whether there is a manufacturing or formulation effect on the vaccine. The study will enroll approximately 1000 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the four study groups-which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need): Group A: TDV Liquid Formulation 1, subcutaneous (SC) injection on Day 1 and placebo (dummy) SC at Month 3 - this is a liquid that looks like the study drug but has no active ingredient Group B: TDV Liquid Formulation 1, SC injection Day 1 and Month 3 Group C: TDV Liquid Formulation 2, SC injection Day 1 and Month 3 Group D: TDV Lyophilized formulation SC injection Day 1 and Month 3 In order to keep the treatment arms undisclosed to the participant and the doctor, participants will receive a placebo injection at any study visit where TDV is not being administered (Month 3). Participants will be asked to record any adverse events that may be related to the vaccine or the injection in a diary card for 28 days after each vaccination. This multi-center trial will be conducted in the United States. The overall time to participate in this study is up to 10 months. Participants will make 9 visits to the clinic including a final visit 1 month after last dose of study drug for a follow-up assessment. A follow up phone call will be done 6 months after the last dose to assess serious adverse events.

Official Title
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A Randomized, Double Blind, Phase 2 Study to Assess the Safety and Immunogenicity of Three Formulations of Takeda's Tetravalent Dengue Vaccine Candidate (TDV) in Healthy Adults

Conditions
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Dengue Fever

Intervention / Treatment
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* Drug: TDV Liquid Formulation 1
* Drug: TDV Liquid Formulation 2
* Drug: TDV IDT Lyophilized
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is aged 18 to 49 years, at the time of enrollment inclusive. 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. 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. Individuals who can comply with trial procedures and are available for the duration of follow-up. Exclusion Criteria: Febrile illness (temperature ≥ 38°C or 100.4°F) or moderate or severe acute illness or infection at the time of enrollment. Trial entry should be delayed until the illness has improved. 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 participants due to participation in the trial, including but not limited to: a. Known hypersensitivity or allergy to any of the vaccine components; b. Individuals with history of substance or alcohol abuse within the past 6 months; c. Female participants who are pregnant or breastfeeding; d. Individuals with any serious chronic or progressive disease according to judgment of the investigator (e.g., neoplasm, insulin dependent diabetes, cardiac, renal or hepatic disease, neurologic or seizure disorder or Guillain-Barré syndrome); e. 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 (use of inhaled, intranasal, or topical corticosteroids is allowed); 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; iii. Administration of immunoglobulins and/or any blood products within the three months preceding the first administration of the investigational vaccine or planned administration during the trial; iv. Receipt of immunostimulants within 60 days prior to Day 1; v. Immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within 6 months preceding (first) vaccination; vi. human immunodeficiency virus (HIV) infection or HIV-related disease; vii. Genetic immunodeficiency. Individuals who received any other vaccines 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 investigational vaccine administration. Individuals participating in any clinical trial with another investigational product 30 days prior to first trial visit or intent to participate in another clinical trial at any time during the conduct of this trial. Individuals who are first degree relatives of individuals involved in trial conduct. If female of childbearing potential, sexually active, and has not used any of the acceptable contraceptive methods for at least 2 months prior to trial entry: a. Of childbearing potential is defined as status post onset of menarche and not meeting any of the following conditions: menopausal (for at least 2 years), 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 one 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 the participants' trial entry. If female of childbearing potential, sexually active and refuses to use an acceptable contraceptive method through to 6 weeks after the last dose of investigational vaccine. Individuals with body mass index (BMI) greater than or equal to 35. Participants who received previous vaccination (in a clinical trial or with an approved product) against flaviviruses including dengue, yellow fever (YF), West Nile (WN), Japanese Encephalitis (JE), and St. Louis encephalitis. Documented or suspected disease caused by dengue, JE, WN, YF virus, and/or St. Louis encephalitis. History of travel to dengue endemic areas including the Caribbean, Mexico, Central America, South America or Southeast Asia during the 6 months prior to screening or planned travel to a dengue endemic area during the study period. Clinically significant abnormality in the screening laboratory tests as judged by the Investigator. History of recurring headaches or migraines (more frequent than once per week) or on prescription medication for treatment of recurring headaches or migraines. Blood tests positive for antibodies to HIV-1/2, Hepatitis C and Hepatitis B surface antigen.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 49 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group A: TDV Liquid + Placebo<br>Takeda's Tetravalent Dengue Vaccine Candidate (TDV) Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1, and TDV Liquid Formulation placebo-matching solution, subcutaneous injection, once on Day 90 (Month 3). | Drug: TDV Liquid Formulation 1<br>* TDV Liquid Formulation 1 for subcutaneous injection<br>Drug: Placebo<br>* TDV liquid formulation placebo-matching solution for subcutaneous injection<br>|
| Active Comparator: Group B: TDV Liquid<br>TDV Liquid Formulation 1, diluted 1:5 with vaccine diluent, subcutaneous injection on Day 1 and Day 90 (Month 3). | Drug: TDV Liquid Formulation 1<br>* TDV Liquid Formulation 1 for subcutaneous injection<br>|
| Experimental: Group C: TDV Liquid<br>TDV Liquid Formulation 2, subcutaneous injection on Day 1 and Day 90 (Month 3). | Drug: TDV Liquid Formulation 2<br>* TDV Liquid Formulation 2 for subcutaneous injection<br>|
| Experimental: Group D: TDV Lyophilized<br>TDV Lyophilized Formulation reconstituted with water, subcutaneous injection on Day 1 and Day 90 (Month 3). | Drug: TDV IDT Lyophilized<br>* TDV Lyophilized Formulation for subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titer (GMT) of Neutralizing Antibodies for Each of the Four Dengue Serotypes Comparing Group D To Groups A and B Combined | Geometric mean titer (GMT) of neutralizing antibodies for each of the four dengue serotypes as measured by Plaque Reduction Neutralization Test resulting in 50% reduction in Plaques (PRNT50). The four dengue serotypes are DEN-1, DEN-2, DEN-3 and DEN-4. A 90% Confidence Interval (CI) for the ratio of GMT (or equivalently the difference of the log transformed GMT) was provided, for each serotype, for the comparison of the lyophilized formulation (Group D) versus the liquid formulation 1 (Groups A+B combined). An Analysis of Variance (ANOVA) model for the natural log-transformed GMT at month 1 with study group as a factor was used for analysis. | Month 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Titers (GMT) of Neutralizing Antibodies for Each of the Four Dengue Serotypes Comparing Group D With Group B | Geometric mean titer (GMT) of neutralizing antibodies for each of the four dengue serotypes as measured by Plaque Reduction Neutralization Test resulting in 50% reduction in Plaques (PRNT50). The four dengue serotypes are DEN-1, DEN-2, DEN-3 and DEN-4. ANOVA model for the natural log-transformed GMT at month 1 with study group as a factor was used for analysis. | Months 1 and 4 | 
| Percentage of Participants With a Seropositive Response for Each of the Four Dengue Serotypes Comparing Group D With Groups A and B Combined | A seropositive response is defined as a reciprocal neutralizing titer ≥ 10. The four dengue serotypes are DEN-1, DEN-2, DEN-3 and DEN-4. | Month 1 | 
| Percentage of Participants With a Seropositive Response for Each of the Four Dengue Serotypes Comparing Group D With Group B | A seropositive response is defined as a reciprocal neutralizing titer ≥ 10. The four dengue serotypes are DEN-1, DEN-2, DEN-3 and DEN-4. | Months 1 and 4 | 
| Percentage of Participants With Solicited Local (Injection Site) Adverse Events (AEs) | Solicited local AEs at injection site are defined as pain, erythema and swelling that occurred at least once within 7 days after either vaccination, as recorded by the participants in a diary. Percentages are based on the number of participants with diary data available. | Days 1 through 7 after each vaccination | 
| Percentage of Participants With Solicited Systemic Adverse Events (AEs) | Solicited systemic AEs are defined as asthenia, fever, headache, malaise, and myalgia that occurred at least once within 14 days after either vaccination, as recorded by the participants in a diary. Percentages are based on the number of participants with diary data available. | Days 1 through 14 after each vaccination | 
| Percentage of Participants With Solicited Local (Injection Site) Adverse Events (AEs) by Severity | The percentage of participants with solicited local AEs at injection site of varying severity are reported. Solicited local AEs are defined as pain, erythema and swelling that occurred at least once within 7 days after either vaccination, as recorded by the participants in a diary. Participants with multiple episodes are categorized using the highest severity level. Percentages are based on the number of participants with diary data available. | Days 1 through 7 after each vaccination | 
| Percentage of Participants With Solicited Systemic Adverse Events (AEs) by Severity | The percentage of participants with solicited systemic AEs of varying severity are reported. Solicited systemic AEs are defined as asthenia, fever, headache, malaise, and myalgia that occurred at least once within 14 days after either vaccination, as recorded by the participants in a diary. Participants with multiple episodes are categorized using the highest severity level. Percentages are based on the number of participants with diary data available. | Days 1 through 14 after each vaccination | 
| Percentage of Participants With Any Unsolicited Adverse Events (AEs) | Unsolicited AEs are any AEs that are not solicited local or systemic AEs, as defined by this study, that occurred at least once within 28 days after either 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. The investigator assessed whether the AE was related to the study vaccination. | Up to Day 28 after each vaccination | 
| Percentage of Participants With Serious Adverse Events (SAEs) | A serious adverse event (SAE) is defined as 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. | Up to 6 Months after the last dose (9 months) | 
| Percentage of Participants With Markedly Abnormal Laboratory Values in the Safety Sub-Set | Percentage of participants with markedly abnormal standard safety laboratory values collected at any time after the first vaccination. | Days 8, 15, 91, 97 and 104 | 

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