Safety and Immunogenicity Study to Assess TDV, a Live Attenuated Tetravalent Vaccine for Prevention of Dengue Fever

Study Overview
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Brief Summary
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The purpose of this study is to assess the safety of Takeda's Tetravalent Dengue Vaccine Candidate (TDV) (previously DENVax) in healthy adults when given as either a subcutaneous (SC) or intradermal (ID) injection at two dose levels (low and high). The vaccine will be given as two doses 90 days apart. Safety assessments include injection site evaluation and adverse events. The immune response generated after vaccination will be assessed up to 9 months after the first vaccination.

Detailed Description
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This is a single center, placebo-controlled, randomized study assessing the safety and tolerability of two dose levels (low and high) of TDV administered subcutaneously or intradermally in two doses separated by an interval of 90 days. Initial dosing of low dose cohort will be performed and Day 21 safety assessed prior to administration of second dose to low dose cohort on Day 90 and initial dosing of high dose cohort. Day 21 safety for the high dose cohort will be assessed prior to administration of second dose for this cohort. Safety (local injection site reactions and solicited and unsolicited adverse events) will be assessed through Day 120 post-first (1 month after the second dose). Immunogenicity will be assessed at specified time points up to Day 120 post-prime (1 month after the second dose) and again on Days 180 and 270 (6 and 9 months post-first).

Official Title
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Phase I, Randomized, Double-blind, Placebo-controlled, Dose-escalation Study to Assess the Safety and Immunogenicity of DENVax Vaccine in Healthy Adults

Conditions
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Dengue Fever

Intervention / Treatment
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* Biological: TDV - Low Dose
* Biological: TDV - High Dose
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Is male or female aged 18 to 45 years, inclusive, at time of screening. Is in good health as determined by medical history, physical examination, and clinical safety laboratory examinations. Has body mass index (BMI) in the range 18-27 kilogram per square meter (kg/m^2). Has negative serology for Human Immunodeficiency Virus (HIV), Hepatitis C antibody, and Hepatitis B surface antigen. Females of child bearing potential must have a negative urine pregnancy test result during screening and a negative urine pregnancy test immediately prior to vaccination and be willing to use oral, implantable, transdermal or injectable contraceptives or another reliable means of contraception approved by the Investigator (intrauterine device, female condom, diaphragm with spermicidal, cervical cap, use of condom by the sexual partner or a sterile sexual partner, or abstinence) from screening until after the last blood sample (at Day 270). Is willing and able to give written informed consent to participate. Is willing and able to communicate with the Investigator and understand the requirements of the study. Exclusion Criteria: Has any condition which would limit the participant's ability to complete the study. Clinically significant hematological, renal, hepatic, pulmonary, central nervous system, cardiovascular or gastrointestinal disorders. Has abnormal electrocardiogram (ECG). Has febrile illness (temperature greater than or equal to (>=) 38 degree Celsius (°C) or 100.4 degree Fahrenheit (°F) or moderate or severe acute illness or infection within three days of vaccination. Diabetes mellitus. Has allergy to penicillin, neomycin, streptomycin or gentamicin. Hypersensitivity to any vaccine. Seropositivity to any of the four dengue serotypes (TDV-1, TDV-2, TDV-3 or TDV-4), yellow fever (YF) virus or West Nile (WN) virus. Has previous vaccination (in a clinical trial or with an approved product) against flaviviruses including dengue, YF or WN. Has planned vaccination against YF throughout the duration of this study. Has receipt of any vaccine in the 4 weeks preceding the first trial vaccination. Planned receipt of any vaccine in the 4 weeks following each of the vaccinations in this study. Travel to dengue-endemic areas in the two months prior to study start or planned travel to dengue-endemic areas during the study period, including low altitude regions of Colombia where dengue is endemic. Known or suspected congenital or acquired immunodeficiency, immunosuppressive therapy such as anti-cancer chemotherapy or radiation therapy within the preceding 6 months prior to the first vaccination, or long- term (at least 2 weeks within the previous 3 months) systemic corticosteroids therapy (at a dose of at least 0.5 milligram per kilogram per day [mg/kg/day]) prior to the first vaccination. Has a history of recurring migraines or on prescription medication for treatment of recurring headaches or migraines. Use of any non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen or antihistamines for the 3 days immediately prior to each vaccination. Use of prescription or over the counter medications 7 days before the first vaccination (Day 0), excluding contraceptives and painkillers containing NSAIDs or acetaminophen, cold remedies, hormone replacement and antihistamines. Positive urine screen for cocaine, amphetamines, opiates, or cannabinoids. Receipt of any other investigational product or participation in any other clinical trial in the month before the first vaccination (Day 0) or during the conduct of this study. Receipt of blood products or immunoglobulins 8 weeks before the first vaccination (Day 0) or planned use during the study period. Donation of blood 6 weeks before the first vaccination (Day 0) or at any time during the study. Females who are pregnant or lactating.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: Low Dose; SC<br>TDV-1: 8 x 10^3 Plaque Forming Units (PFU), TDV-2: 5 x 10^3 PFU, TDV-3: 1 x 10^4 PFU, TDV-4: 2 x 10^5 PFU or placebo administered subcutaneously on Days 0 and 90. Dose volume is 0.5 mL. | Biological: TDV - Low Dose<br>* TDV is a tetravalent dengue vaccine comprised of four recombinant, live attenuated dengue virus strains: TDV-1, TDV-2, TDV-3 and TDV-4. Low dose contains: TDV-1: 8 x 10^3 PFU, TDV-2: 5 x 10^3 PFU, TDV-3: 1 x 10^4 PFU, and TDV-4: 2 x 10^5 PFU, total virus per dose 2.2 x 10^5 PFU<br>* Other names: Live attenuated tetravalent dengue vaccine;|
| Experimental: Group 2: Low Dose; ID<br>TDV-1: 8 x 10^3 PFU, TDV-2: 5 x 10^3 PFU, TDV-3: 1 x 10^4 PFU, TDV-4: 2 x 10^5 PFU or placebo administered intradermally on Days 0 and 90. Dose volume is 0.1 mL. | Biological: TDV - Low Dose<br>* TDV is a tetravalent dengue vaccine comprised of four recombinant, live attenuated dengue virus strains: TDV-1, TDV-2, TDV-3 and TDV-4. Low dose contains: TDV-1: 8 x 10^3 PFU, TDV-2: 5 x 10^3 PFU, TDV-3: 1 x 10^4 PFU, and TDV-4: 2 x 10^5 PFU, total virus per dose 2.2 x 10^5 PFU<br>* Other names: Live attenuated tetravalent dengue vaccine;|
| Experimental: Group 3: High Dose; SC<br>TDV-1: 2 x 10^4 PFU, TDV-2: 5 x 10^4 PFU, TDV-3: 1 x 10^5 PFU, TDV-4: 3 x 10^5 PFU or placebo administered subcutaneously on Days 0 and 90. Dose volume is 0.5 mL. | Biological: TDV - High Dose<br>* TDV is a tetravalent dengue vaccine comprised of four recombinant, live attenuated dengue virus strains: TDV-1, TDV-2, TDV-3 and TDV-4. High dose contains TDV-1: 2 x 10^4 PFU, TDV-2: 5 x 10^4 PFU, TDV-3: 1 x 10^5 PFU, and TDV-4: 3 x 10^5 PFU, total virus per dose : 4.7 x 10^5 PFU. TDV administered intradermally.<br>* Other names: Live attenuated tetravalent dengue vaccine;|
| Experimental: Group 4: High Dose; ID<br>TDV-1: 2 x 10^4 PFU, TDV-2: 5 x 10^4 PFU, TDV-3: 1 x 10^5 PFU, TDV-4: 3 x 10^5 PFU or placebo administered intradermally on Days 0 and 90. Dose volume is 0.1 mL. | Biological: TDV - High Dose<br>* TDV is a tetravalent dengue vaccine comprised of four recombinant, live attenuated dengue virus strains: TDV-1, TDV-2, TDV-3 and TDV-4. High dose contains TDV-1: 2 x 10^4 PFU, TDV-2: 5 x 10^4 PFU, TDV-3: 1 x 10^5 PFU, and TDV-4: 3 x 10^5 PFU, total virus per dose : 4.7 x 10^5 PFU. TDV administered intradermally.<br>* Other names: Live attenuated tetravalent dengue vaccine;|
| Placebo Comparator: Placebo (SC)<br>Phosphate buffered saline administered subcutaneously in a volume of 0.5 mL. | Biological: Placebo<br>* Phosphate Buffered Saline (PBS)<br>* Other names: PBS;|
| Placebo Comparator: Placebo (ID)<br>Phosphate buffered saline administered intradermally in a dose volume of 0.1 mL. | Biological: Placebo<br>* Phosphate Buffered Saline (PBS)<br>* Other names: PBS;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Local Injection Site Reaction by Severity | Solicited local reactions were reported using a participant diary. Pain was categorized as Mild (aware of pain but it does not interfere with daily activity and no pain medication is taken); Moderate (aware of pain; there is interference with daily activity or it requires use of pain medication); Severe (aware of pain and it prevents daily activity), redness was categorized as Mild (greater than [>] 15 millimeter [mm]); Moderate as (15-30 mm); Severe (>30 mm), swelling was categorized as Mild (<15 mm); Moderate (15-30 mm); Severe (>30 mm), and itching was categorized as Mild (slight itching at injection site); Moderate (moderate itching at injection extremity); Severe (itching over entire body). | Within 14 days after either of the vaccination given on Day 1 or 90 (Day 14 for first vaccination, Day 104 for second vaccination) | 
| Number of Participants With Systemic Adverse Events (AEs) by Severity | Solicited systemic AEs were reported using a participant diary. Solicited systemic AEs included fever (>= 37.8°C), headache, muscle pain, joint pain, eye pain, photophobia, fatigue, body rash, nausea, vomiting and other (any other symptom not listed in the diary) and were categorized as Mild: transient symptoms, discomfort noticed but easily tolerated, no interference to normal daily activities; Moderate: marked symptoms, moderate interference with daily activities; Severe: considerable interference with daily activities. | Within 14 days after either of the vaccination given on Day 1 or 90 (Day 14 for first vaccination, Day 104 for second vaccination) | 
| Number of Participants With Solicited Local and Systemic AEs |  | Within 14 days after either of the vaccination given on Day 1 or 90 (Day 14 for first vaccination, Day 104 for second vaccination) | 
| Number of Participants With Unsolicited Local and Systemic AEs |  | Baseline up to 30 days after second vaccination (Day 120) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Geometric Mean Neutralizing Antibody Titers (GMTs) of All Four Dengue Serotypes After First Vaccination | GMT was assessed for the four dengue serotypes: Dengue TDV-1, TDV-2, TDV-3 and TDV-4. GMTs and 95 percent (%) confidence interval (CIs) were calculated by taking the anti-logs of the means and 95% CI of the log transformed titers. | Days 14, 30, 60 and 90 after first vaccination | 
| GMTs of All Four Dengue Serotypes After Second Vaccination | GMT was assessed for the four dengue serotypes: TDV-1, TDV-2, TDV-3 and TDV-4. GMTs and 95% CIs were calculated by taking the anti-logs of the means and 95% CI of the log transformed titers. | Days 14 and 30 after second vaccination (Day 104 and 120 respectively) | 
| Rate of Seroconversion to Each of Four Dengue Serotypes After the First Vaccination | Seroconversion was defined as a Plaque Reduction Neutralization Test (PRNT) titer resulting in 50% reduction in plaques (PRNT[50]) >=10 (if the pre-vaccination PRNT[50] value was <10, indicated as a value of 5 in the immunogenicity data collection sheet) OR a PRNT(50) value that was >=4-fold the pre-vaccination titer value (if the pre-vaccination PRNT[50] value was >=10). Seroconversion was assessed for the four dengue serotypes: TDV-1, TDV-2, TDV-3 and TDV-4. The 95% CIs for percentages are the exact CIs (%) based upon the binomial distribution. Percentages are based on the number of participants in the FAS with non-missing MN assay samples at each visit. | Days 14, 30, 60 and 90 after first vaccination | 
| Rate of Seroconversion to Each of Four Dengue Serotypes After the Second Vaccination | Seroconversion was defined as a PRNT titer resulting in 50% reduction in plaques (PRNT[50]) >=10 (if the pre-vaccination PRNT[50] value was <10, indicated as a value of 5 in the immunogenicity data collection sheet) OR a PRNT(50) value that was >=4-fold the pre-vaccination titer value (if the pre-vaccination PRNT[50] value was >=10). Seroconversion was assessed for the four dengue serotypes: TDV-1, TDV-2, TDV-3 and TDV-4. The 95% CIs for percentages are the exact CIs (%) based upon the binomial distribution. Percentages are based on the number of participants in the FAS with non-missing MN assay samples at each visit (n). | Days 14 and 30 after second vaccination (Days 104 and 120 respectively) | 
| Percentage of Participants With Durability of Immune Response | Immune response was considered durable if the participant had detectable neutralizing antibodies (seroconversion) to all 4 dengue serotypes at 90 and 180 days after the second dose (i.e. Days 180 and 270, respectively). Seroconversion is defined as post-vaccination PRNT(50) titer >=10 where pre-vaccination PRNT 50 titer <10, or post-vaccination PRNT(50) Titer >=4-fold the pre-vaccination PRNT(50) titer value where pre-vaccination PRNT(50) titer >=10. Percentage of participants with seroconversion on Days 180 and 270 are based on the number of participants in the FAS with non-missing MN assay samples at each visit. The 95% CIs for percentages are the exact CIs (%) based upon the binomial distribution. | Days 180 and 270 | 
| Number of Participants Positive for Vaccine Viremia for Each of the Four Vaccine Strain Serotypes After the First and Second Vaccination | Serotype-specific vaccine viremia was assessed for the four vaccine strain serotypes: TDV-1, TDV-2, TDV-3 and TDV-4. Only those serotypes and time-points where at least 1 participant had serotype-specific vaccine viremia detection were reported. | Baseline and at multiple time points up to Day 14 after each vaccination | 
| Duration of Vaccine Viremia |  | 14 Days after each vaccination | 
| Titers of Vaccine Viremia |  | 14 Days after each vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TDV, dengue fever, live attenuated tetravalent dengue vaccine, Drug therapy